Novel pharmacological mechanism to block stress-induced cortisol production

Abstract

Methods for reducing stress-induced hormone production and treating a disease, disorder, or condition associated with an increase in stress-induced hormones by administering a therapeutically effective amount of a glutamate carboxypeptidase II (GCPII) inhibitor to a subject in need of treatment are disclosed.

Description

NOVEL PHARMACOLOGICAL MECHANISM TO BLOCK STRESS-INDUCEDCORTISOL PRODUCTIONFEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0001] This invention was made with government support under grant AG068130 and AG078181 awarded by the National Institutes of Health. The government has certain rights in the invention.BACKGROUND

[0002] Glutamate carboxypeptidase II (GCPII) is a membrane-bound peptidase expressed in the brain, prostate, intestines, and kidneys. GCPII is the catabolic enzyme of the abundant neuropeptide N-acetylaspartylglutamate (NAAG) cleaving it into N-acetylaspartate (NAA) and glutamate. To date, however, the role of GCPII in regulating the production of stress hormones has not been investigated.SUMMARY

[0003] In some aspects, the presently disclosed subject matter provides a method for reducing stress-induced hormone production in a subject in need thereof, the method comprising administering a therapeutically effective amount of a glutamate carboxypeptidase II (GCPII) inhibitor to the subject.

[0004] In certain aspects, the stress hormone is selected from aldosterone, corticosterone, and a combination thereof. In particular aspects, the GCPII inhibitor is 2-(phosphonomethyl)- pentanedioic acid (2-PMPA), or an analog, a prodrug, a nanomedicine formulation, or a dendrimer thereof.

[0005] In certain aspects, administering the therapeutically effective amount of the GCPII inhibitor comprises blocking a stress-induced increase in plasma levels of the stress-induced hormone. In particular aspects, the blocking of the stress-induced increase in plasma levels of the stress-induced hormone has no effect on a basal level of the stress-induced hormone.

[0006] In other aspects, the presently disclosed subject matter provides a method for treating a disease, disorder, or condition in a subject in need of treatment thereof, the method comprising reducing stress-induced hormone production in the subject by administering a therapeutically effective amount of a glutamate carboxypeptidase II (GCPII) inhibitor to the subject.

[0007] In certain aspects, the disease, disorder, or condition comprises a stress-related psychiatric disorder. In particular aspects, the stress-related psychiatric disorder is selected from depression, anxiety, bipolar disorder, and obsessive-compulsive disorder.

[0008] In certain aspects, the disease, disorder, or condition comprises a neurodegenerative disease. In particular aspects, the neurodegenerative disease is selected from Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, multiple sclerosis, muscular dystrophy, and Huntington's disease. In more particular aspects, the method comprises slowing onset or progression of Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, multiple sclerosis, muscular dystrophy, and Huntington's disease.

[0009] In certain aspects, the disease, disorder, or condition comprises a cardiovascular disease. In certain aspects, the method comprises reducing a risk of a heart attack or a stroke. In certain aspects, the method comprises lowering one or more clinical conditions regulated by plasma stress hormones. In particular aspects, the one more clinical conditions is selected from blood cholesterol levels, triglyceride levels, blood sugar levels, blood pressure, and arterial stiffness.

[0010] In certain aspects, the disease, disorder, or condition comprises Cushing syndrome.

[0011] Certain aspects of the presently disclosed subject matter having been stated hereinabove, which are addressed in whole or in part by the presently disclosed subject matter, other aspects will become evident as the description proceeds when taken in connection with the accompanying Examples and Drawings as best described herein below.BRIEF DESCRIPTION OF THE FIGURES

[0012] The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawings will be provided by the Office upon request and payment of the necessary fee.

[0013] Having thus described the presently disclosed subject matter in general terms, reference will now be made to the accompanying Figures, which are not necessarily drawn to scale, and wherein:

[0014] FIG. 1 demonstrates that chronic GCPII inhibition increases NAAG levels in plasma. 15- month-old C57BL / 6 mice were treated with the potent GCPII inhibitor 2-PMPA (100 mg / kg, i.p.) or vehicle (HEPES buffer) 5 days per week for 10 months. GCPII inhibition led to a 3.5-fold increase in plasma NAAG levels.

[0015] FIG. 2A and FIG. 2B demonstrate that chronic GCPII inhibition decreases aldosterone and corticosterone levels in plasma. 15-month-old C57BL / 6 mice were treated with the potent GCPII inhibitor 2-PMPA (100 mg / kg, i.p.) or vehicle (HEPES buffer) 5 days per week for 10 months. GCPII inhibition led to an approximately 80% decrease in plasma aldosterone and corticosterone levels.

[0016] FIG. 3 demonstrates GCPII inhibition relieves stress-induced increases in corticosterone and aldosterone levels in plasma in mice following chronic social defeat stress. Male C57BL / 6 mice were subjected to chronic social defeat stress (CSDS) by daily 10 min exposure to aggressive male CD-I mice for 10 consecutive days. Non-stressed control C57 mice were housed without CD-I exposure. During CSDS exposure, C57 mice displayed hallmark defeat behaviors including escape, submissive posturing, and freezing. C57 mice were maintained in the CSDS condition for 10 days and treated daily with the GCPII inhibitor 2-PMPA (100 mg / kg, i.p.) or vehicle (HEPES buffer) control. GCPII inhibition prevented stress-induced increases in plasma corticosterone and aldosterone levels.

[0017] FIG. 4 demonstrates that GCP knockout (KO) suppresses CSDS-induced upregulation of plasma steroid levels. CSDS significantly increased plasma corticosterone (CORT) and aldosterone (ALDO) levels in WT mice (CSDS W) compared to control WT mice (CTR W). In contrast, GCP KO mice exposed to CSDS (CSDS G) showed plasma steroid levels similar to those of control KO mice (CTR G).

[0018] FIG. 5 demonstrates that GCP KO improved recognition memory deficits induced by CSDS. In the Novel object recognition test (NORT), CSDS W mice showed significantly reduced exploration of the novel object compared to CTR W, indicating impaired recognition memory. In contrast, CSDS G mice spent a significantly greater percentage of time sniffing the novel object compared to CSDS W.

[0019] FIG. 6 demonstrates that GCP KO alleviated social avoidance induced by CSDS. In the Social interaction test (SIT), CSDS W mice exhibited social avoidance, reflected by reduced time spent in the chamber with the stranger mouse and less sniffing interaction. CSDS G mice spent significantly more time in the chamber with the stranger mouse and engaged in prolonged sniffing compared to CSDS W mice.DETAILED DESCRIPTION

[0020] The presently disclosed subject matter now will be described more fully hereinafter with reference to the accompanying Figures, in which some, but not all embodiments of the inventions are shown. Like numbers refer to like elements throughout. The presently disclosed subject matter may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will satisfy applicable legal requirements. Therefore, it is to be understood that the presently disclosed subject matter is not to be limited to the specific embodiments disclosed and that modifications and other embodiments are intended to be included within the scope of the appended claims.

[0021] The presently disclosed subject matter is directed to the discovery that pharmacological inhibition of GCPII’ s enzymatic activity blocks the stress-induced increases in plasma aldosterone and corticosterone, while having no effect on the basal levels of these hormones.

[0022] The ability to regulate the production of stress hormones could have widespread therapeutic impact including on multiple stress-related psychiatric disorders, including depression, anxiety, bipolar disorder, and obsessive-compulsive disorder.

[0023] Moreover, since chronic stress can increase the risk of neurodegenerative diseases, GCPII inhibition could provide profound beneficial effects for slowing the onset or progression of disorders such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, multiple sclerosis, muscular dystrophy, and Huntington's disease. Beyond neurological applications, GCPII inhibition could improve cardiovascular diseases related to stress by beneficially impacting blood cholesterol, triglycerides, blood sugar, blood pressure, arterial stiffness, and reducing heart attack and stroke risk, as these are known to be regulated by plasma stress hormones. In addition, GCPII inhibition could have benefits for Cushing syndrome which happens when the body has too much production of cortisol for a long time. Accordingly, the presently disclosed subject matter can potentially redefine treatment options for many diseases, disorders, or conditions associated with detrimental cortisol increases.

[0024] In some embodiments, the presently disclosed subject matter provides a method for reducing stress-induced hormone production in a subject in need thereof, the method comprising administering a therapeutically effective amount of a glutamate carboxypeptidase II (GCPII) inhibitor to the subject.

[0025] In certain embodiments, the GCPII inhibitor is 2-(phosphonomethyl)-pentanedioic acid (2- PMPA), or an analog, a prodrug, a bile acid conjugate, a nanomcdicinc formulation, or a dendrimer thereof.

[0026] GCPII inhibitors generally fall into the following representative classes including, but not limited to, phosphonates, including bile acid conjugates of phosphonates, such as 2-PMPA, phosphinates, phosphoramidates, thiols, hydroxamates, and ureas:wherein R1, R2, R3, R’3, and R4are substituent groups as defined herein. See, for example, Vornov et al., 2020; Past.orino et al.. 2020; Gourni and Henriksen, 2017; Barinka et. al., 2012,

[0031] Known GCPII inhibitors representative of these general classes include 2- (phosphonomethyl) pentanedioic acid (2-PMPA) (phosphonates), 2-(3- mercaptopropyl)pentanedioic acid (2-MPPA) (thiols), 2-(2-(hydroxyamino)-2- oxoethyl)pentanedioic acid (JHU 241) (hydroxamates), see also Rais et al., 2017, for other hydroxamatc-bascd glutamate GCPII inhibitors, including, 4-carboxy-alpha-[3-(hydroxyamino)- 3-oxopropyl]-benzenepropanoic acid, and A-[N-[(S)]-l,3-dicarboxypropyl] carbamoyl] -L-leucine (ZJ-43) (ureas):

[0032]

[0033]

[0034] See, for example, Vornov et al., 2020.

[0035] Other phosphonate-based GCPII inhibitors include GPI-5232, Jackson and Slusher, 2001, and VA-033, Ding et al., 2004:

[0037] Examples of these classes of GCPII inhibitors are presented herein below.

[0038] Bile Acid Conjugates with 2-(phosphonomethyl) pentanedioic acid (2-PMPA)

[0039] In some embodiments, the presently disclosed GCPII inhibitors can be formed by conjugating the potent GCPII inhibitor 2-(phosphonomethyl) pentanedioic acid (2-PMPA) to a bile acid. The chemical formula of 2-PMPA is provided immediately herein below:

[0040]

[0041] Bile acids, which are abundant endogenously, were selected as the conjugate as they also are reported to have direct immunomodulatory effects in a variety of inflammatory models, Sipka and Bruckner, 2014; Calmus and Poupon, 2014; Ho and Steinman, 2016, including protection in IBD models. Laukens, et al., 2014. Bile acids have the following general chemical structure:

[0043] wherein:

[0044] R'1and R'2are each independently H or -OH; R'3is -OH; R'4is selected from the group consisting of -OH, -NHCH2COOH, and -NHCH2CH2SO3H; and salts thereof.

[0045] Representative bile acids include, but are not limited to, cholic acid, glycocholic acid, deoxycholic acid, lithocholic acid, glycodeoxycholic acid, chenodeoxycholic acid (also referred to as chenocholic acid), glycochenodeoxy cholic acid, ursodeoxycholic acid, taurocholic acid, taurodeoxycholic acid, taurochenodeoxycholic acid, and derivatives thereof, the structures of which are provided immediately herein below in Table 1.

[0046] Accordingly, in some embodiments, the presently disclosed subject matter provides a conjugate of 2-(phosphonomethyl) pentanedioic acid (2-PMPA), or a derivative thereof, and a bile acid, or derivative thereof. Representative bile acid conjugates of 2-PMPA are disclosed in International PCT Patent Application No. WO2021155167 for Bile Acid-GCPII InhibitorConjugates to Treat Inflammatory Diseases, to Slusher et al., published August 5, 2021 , which is incorporated by reference in its entirety.

[0047] In some embodiments, the conjugate comprises a compound of formula (I):

[0049] wherein: R1and R2are each independently H or -OH; R3is OH; and R4is selected from the group consisting of -NH-X1, -COO-X1, -C(=O)-NH-CH2-C(=O)-O-X1, and -C(=O)-NH- CH2-CH2-S(=O)2-O-X1, wherein X1is selected from the group consisting of -(C=O)-(CH2)m- P(=O)(OH)-X2, -(C=O)-(CH2)m-CH(COOH)-CH2-P(=O)(OH)-X2, -CH2-O-(C=O)-(CH2)m- P(=O)(OH)-X2, -CH2-O-C(=O)-(CH2)m-CH(COOH)-CH2-P(=O)(OH)-X2, -CH2-O-C(=O)- (CH2)m-CH(COOH)-NH-(C=O)-NH-CH(COOH)-CH2-CH(CH3)2, -CH2-O-C(=O)-Ar-CH2- CH(COOH)-(CH2)m-C(=O)-NH-OH, -CH2-O-C(=O)-(CH2)m-X3, -CH2-O-C(=O)-Ar-CH2-X3, and a protecting group, wherein X2is selected from the group consisting of -OH, -CH2-CH(COOH)- (CH2)p-C(=O)-OH, and a protecting group, Ar is arylene, and X3is 2-oxotetrahydro-2H-thiopyran- 3-yl, and each m and p is independently selected from the group consisting of 1, 2, 3, and 4; or R3is selected from the group consisting of -O-C(=O)-O-CH2-O-C(=O)-(CH2)n-CH(COOH)-CH2- P(=O)(OH)2, and -O-C(=O)-CH2-CH2-P(=O)(OH)-CH2-CH(COOH)-(CH2)n-C(=O)-OH, wherein each n is independently an integer selected from the group consisting of 1, 2, 3, and 4; and R4is selected from the group consisting of -NH2, -COOH, -C(=O)-NH-CH2-C(=O)-OH, and -C(=O)- NH-CH2-CH2-S(=O)2-OH; and pharmaceutically acceptable salts thereof.

[0050] In some embodiments, R1and R2are both H. In some embodiments, R1is H and R2is OH. In some embodiments, R1is OH and R2is H. In some embodiments, R1and R2are both OH.

[0051] In some embodiments, R3is OH and R4is selected from the group consisting of -NH-X1, - COO-X1, -C(=O)-NH-CH2-C(=O)-O-X1, and -C(=O)-NH-CH2-CH2-S(=O)2-O-X1, wherein X1is selected from the group consisting of -(C=O)-CH2-CH2-P(=O)(OH)-X2, -(C=O)-CH2-CH2- CH(COOH)-CH2-P(=O)(OH)-X2, -CH2-O-(C=O)-CH2-CH2-P(=O)(OH)-X2, -CH2-O-C(=O)- CH2-CH2-CH(COOH)-CH2-P(=O)(OH)-X2, -CH2-O-C(=O)-CH2-CH2-CH(COOH)-NH-(C=O)- NH-CH(COOH)-CH2-CH(CH3)2, -CH2-O-C(=O)-Ar-CH2-CH(COOH)-CH2CH2-C(=O)-NH-OH,-CH2-O-C(=O)-CH2-CH2-X3, -CH2-O-C(=O)-Ar-CH2-X3, and a protecting group, wherein X2is selected from the group consisting of -OH, -CH2-CH(COOH)-CH2-CH2-CH(=O)-OH, and a protecting group, Ar is phenyl, and X3is 2-oxotetrahydro-2H-thiopyran-3-yl.

[0052] In some embodiments, R1is OH, R2is H, R3is OH, and R4is COO-X1, wherein X1is - CH2-O-C(=O)-(CH2)m-CH(COOH)-CH2-P(=O)(OH)-X2.

[0053] In some embodiments, R1is H and R2is OH or R1is OH and R2is H, R3is OH, and R4is -NH-X1, wherein X1is -(C=O)-CH2-CH2-CH(COOH)-CH2-P(=O)(OH)-X2.

[0054] In some embodiments, the compound of formula (I) is selected from the group consisting

[0060]

[0061]

[0062]

[0063]

[0064]

[0065]

[0070] In some embodiments, R3is selected from the group consisting of -O-C(=O)-O-CH2-O-C(=O)-CH2-CH2-CH(COOH)-CH2-P(=O)(OH)2, and -O-C(=O)-CH2-CH2-P(=O)(OH)-CH2-CH(COOH)-CH2-CH2-C(=O)-OH, and R4is selected from the group consisting of -NH2, -COOH,-C(=O)-NH-CH2-C(=O)-OH, and -C(=O)-NH-CH2-CH2-S(=O)2-OH.

[0071] In such embodiments, the compound of formula (I) is selected from the group consisting of:

[0072]

[0076] Hydro xamate-based GCPII Inhibitors and Prodrugs Thereof

[0077] Hydroxamate-based GCPII inhibitors include 2-(2-(hydroxyamino)-2- oxoethyl)pentanedioic acid (JHU 241) and 4-carboxy-alpha-[3-(hydroxyamino)-3-oxopropyl]- benzenepropanoic acid. See Stoermer et al., 2003; Novakova et al., 2016; and Rais et al., 2017, for other hydroxamate-based glutamate GCPII inhibitors.

[0078] In some embodiments, the GCPII inhibitor is a hydroxamate-based GCPII inhibitor of formula (Ila):

[0079]

[0080] wherein n is an integer selected from 0, 1, 2, and 3. In particular embodiments, the hydroxamate-based GCPII inhibitor comprises:

[0081]

[0082] Representative prodrugs of hydroxamate-based GCPII inhibitors are disclosed in International PCT Patent Application Publication No. WO2018094334 for Prodrugs of Hydroxamate-Based GCPII Inhibitors, to Slusher et al., published May 24, 2018, which is incorporated herein by reference in its entirety, in particular, page 6, line 31, through page 17, line1; U.S. Patent No. 11,059,775 for Prodrug compositions and utility of hydroxamate-based GCPII inhibitors, to Slusher et al., issued July 13, 2021; and U.S. Patent Application Publication No. US 2021-0355079 Al for Prodrug compositions and utility of hydroxamate-based GCPII inhibitors, to Slusher et al., published November 18, 2021, each of which is incorporated herein by reference in its entirety.

[0083] In some embodiments, the presently disclosed subject matter provides prodrugs of hydroxamate-based GCPII inhibitors compound of formula (llb):

[0084]

[0085] wherein: R1is selected from the group consisting of -C(=O)-O-R4and -Ar-C(=O)-O-R4; R2is selected from the group consisting of substituted and unsubstituted C1-C6alkyl, substituted and unsubstituted C3-C8cycloalkyl, substituted and unsubstituted C6-C12aryl, substituted and unsubstituted C6-C12heteroaryl, -(CR5R6jn-R7, -C(=O)-O-R7, -C(=O)-R7.-C(=O)-NR7R8, - (CR5R6)n-O-C(=O)-O-R7, -(CR5R6)n-Ar-O-C(=O)-R7; R3is selected from the group consisting of H, substituted and unsubstituted C1-C6alkyl, substituted and unsubstituted C3-C12cycloalkyl, substituted and unsubstituted C6-C12aryl, substituted and unsubstituted C5-C12heteroaryl; R4is selected from the group consisting of H, substituted and unsubstituted C1-C6alkyl, substituted and unsubstituted C3-C12cycloalkyl, substituted and unsubstituted C6-C12aryl, substituted and unsubstituted C5-C12heteroaryl, -(CR5R6)n-O-C(=O)-O-R9, and -(CR5R6)n-Ar-O-C(=O)-R9; each R5and R6is independently selected from the group consisting of H, C1-C10alkyl, and C6-C12aralkyl; R7is selected from the group consisting of H, and substituted and unsubstituted C1-C10alkyl, substituted and unsubstituted C1-C10heteroalkyl, substituted and unsubstituted C3-C16cycloalkyl, substituted and unsubstituted C3-C12cycloheteroalkyl, substituted and unsubstituted C3-C12cycloheteroalkenyl, substituted and unsubstituted C6-C12aryl, substituted and unsubstitutedC6-C12heteroaryl, and substituted and unsubstituted C6-C12aralkyl; R8is selected from the group consisting of H, and substituted and unsubstituted C1-C6alkyl; R9is selected from the group consisting of H, and substituted and unsubstituted C1-C6alkyl; n is an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, and 6; Ar is selected from the group consisting of substituted and unsubstituted C6-C12aryl, and substituted and unsubstituted C6-C12heteroaryl; and stereoisomers and pharmaceutically acceptable salts thereof.

[0086] In some embodiments, the compound of formula (llb) is selected from the group consisting of:

[0087]

[0088]

[0089] wherein R2, R3, and R4, are as defined hereinabove; and stereoisomers and pharmaceutically acceptable salts thereof.

[0090] In some embodiments, R2is as defined hereinabove; R3is selected from the group consisting of H and substituted and unsubstituted C1-C6alkyl; R4is selected from the group consisting of H, substituted and unsubstituted C1-C6alkyl, -(CR5R6)n-Ar-O-C(=O)-R9, and - (CR5R6)n-O-C(=O)-O-R9; n is 1; R5and R6are H; Ar is phenyl; R9is selected from the group consisting of substituted C1-C3alkyl, and unsubstituted C1-C3alkyl; and stereoisomers and pharmaceutically acceptable salts thereof.

[0091] In some embodiments R2is -(CR5R6)n-Ar-O-C(=O)-R7, n is 1, Ar is phenyl, and R7is substituted or unsubstituted C1-C6alkyl.

[0092] In particular embodiments, the compound of formula (llb) is selected from the group consisting of:

[0093]

[0094]

[0095]

[0096]

[0097] In other embodiments, R2is -(CR5R6)n-R7, n is 1, and R7is substituted C3-C12cyclohetero alkenyl. In particular embodiments, the compound of formula (llb) is selected from the group consisting of:

[0100] In some embodiments R2is -C(=O)-R7, and R7is unsubstituted C1-C6alkyl, substituted C1- C6alkyl, unsubstituted C6-C12aryl, or unsubstituted C6-C12aralkyl. In particular embodiments, the compound of formula (llb) is selected from the group consisting of:

[0106] In some embodiments, R2is -C(=O)-O-R7, and R7is unsubstituted C1-C6alkyl. In particular embodiments, the compound of formula (llb) is:

[0107]

[0108] In some embodiments, R2is -C(=O)-NR7R8, R7is substituted C1-C6alkyl, or substituted C3-C16cycloalkyl, and R8is H. In particular embodiments, the compound of formula (lib) is selected from the group consisting of:

[0111] Phosphonate-based GCPII Inhibitors, including 2-PMPA, and Prodrugs Thereof

[0112] In some embodiments, the GCPII inhibitor is 2-PMPA or a prodrug thereof.

[0113] Representative prodrugs of 2-PMPA are disclosed in International PCT Patent Application Publication No. WO2016022827 for Prodrugs of Prostate Specific Membrane Antigen (PSMA) Inhibitor, to Slusher et al., published February 11, 2016, which is incorporated by reference in its entirety, in particular page 9, line 19, through page 25, line 12.

[0114] In some embodiments, the presently disclosed subject matter provides a compound of formula (Illa) or formula (Illb):

[0116] wherein:

[0117] each R1, R2, R3, and R4is independently selected from the group consisting of H, alkyl, Ar, -( CR5R6)n-Ar, -(CR5R6)n-O-C(=O)-R7, -(CR5R6)n-C(=O)-O-R7, -(CR5R6)n-O-C(=O)-O-R7,- (CR5R6)n-O-R7, -(CR5R6)n-O-[(CR5R6)n-O]m-R7, -(CR5R6)n-Ar-O-C(=O)-R7,-Ar-C(=O)-O-(CR5R6)n-R7, -(CR5R6)n-NR8R9, and -(CR5R6)n-C(=O)-NR8R9;

[0118] wherein:

[0119] n is an integer from 1 to 20;

[0120] m is an integer from 1 to 20;

[0121] each R3' and R4are independently H or alkyl;

[0122] each R5and R6is independently selected from the group consisting of H, alkyl, and alkylaryl;

[0123] each R7is independently straightchain or branched alkyl;

[0124] Ar is aryl, substituted aryl, heteroaryl or substituted heteroaryl; and

[0125] R8and R9are each independently H or alkyl; and

[0126] pharmaceutically acceptable salts thereof.

[0127] In particular embodiments, the compound of formula (Illa) is selected from the group consisting of:

[0128]

[0129] In particular embodiments, the compound of formula (Illa) is selected from the group consisting of:

[0130]

[0131] In particular embodiments, the compound of formula (Illa) is selected from the group consisting of:

[0133] In particular embodiments, the compound of formula (Illa) is selected from the group consisting of:

[0136] In particular embodiments, the compound of formula (Illa) is:

[0138] In particular embodiments, the compound of formula (Illa) is:

[0140] In particular embodiments, the compound of formula (Illa) is:

[0142] In particular embodiments, the compound of formula (Illa) is:

[0144] In particular embodiments, the compound of formula (Illa) is:

[0146] In particular embodiments, the compound of formula (Illa) is:

[0148] In particular embodiments, the compound of formula (Illa) is selected from the group consisting of:

[0150] In particular embodiments, the compound of formula (Illa) is:

[0152] In particular embodiments, the compound of formula (Illa) is:

[0154] In particular embodiments, the compound of formula (Illa) is selected from the group consisting of:

[0156] In particular embodiments, the compound of formula (Illa) is:

[0158] In particular embodiments, the compound of formula (Illa) is:

[0160] In particular embodiments, the compound of formula (Illa) is:

[0162] In particular embodiments, the compound of formula (Illa) is:

[0164] In particular embodiments, the compound of formula (Illa) is selected from the group consisting of:

[0165]

[0166] In particular embodiments, the compound of formula (Illa) is selected from the group consisting of:

[0168] In particular embodiments, the compound of formula (Illa) is selected from the group consisting of:

[0171] In particular embodiments, the compound of formula (Illa) is:

[0172]

[0173] In particular embodiments, the compound of formula (Illa) is selected from the group consisting of:

[0177] In particular embodiments, the compound of formula (Illb) is:

[0179] In particular embodiments, the compound of formula (Illb) is:

[0180]

[0181] In certain embodiments:

[0182] (a) each R1is H;each R2is selected from the group consisting of H, alkyl, Ar, -(CR5R6)n- Ar, -(CR5R6)n-O-C(=O)-R7, -(CR5R6)n- C(=O)-O-R7, -(CR5R6)n-O-C(=O)-O-R7, -(CR5R6)n-O-R7, -(CR5R6)n-O-[(CR5R6)n-O]m-R7, -(CR5R6)n-Ar-O-C(=O)-R7, -Ar-C(=O)-O-(CR5R6)n-R7, - (CR5R6)n-NR8R9, and -(CR5R6)n-C(=O)-NR8R9;each R3is selected from the group consisting of H, alkyl, Ar, -(CR5R6)n-Ar, -(CR5R6)n-O-C(=O)-R7, -(CR5R6)n- C(=O)-O-R7, -(CR5R6)n-O-C(=O)- O-R7, -(CR5R6)n-O-R7, -(CR5R6)n-O-[(CR5R6)n-O]m-R7, -(CR5R6)n-Ar-O-C(=O)-R7, -Ar-C(=O)- O-(CR5R6)n-R7, -(CR5R6)n-NR8R9, and -(CR5R6in-C(=O)-NR8R9; and each R4is selected from the group consisting of -(CR5R6)n-O-C(=O)-R7, -(CR5R6)n- C(=O)-O-R7, -(CR5R6)n-O-C(=O)-O-R7, - (CR5R6)n-O-R7, -(CR5R6)n-O-[(CR5R6)n-O]m-R7, -(CR5R6)n-Ar-O-C(=O)-R7, -Ar-C(=O)-O- (CR5R6)n-R7, -(CR5R6)n-NR8R9, and -(CR5R6)n-C(=O)-NR8R9;

[0183] (b) each R1is alkyl; each R2is selected from the group consisting of H, alkyl, Ar, - (CR5R6)n-Ar, -(CR5R6)n-O-C(=O)-R7, -(CR5R6)n- C(=O)-O-R7, -(CR5R6)n-O-C(=O)-O-R7, - (CR5R6)n-O-R7, -(CR5R6)n-O-[(CR5R6)n-O]m-R7, -(CR5R6)n-Ar-O-C(=O)-R7, -Ar-C(=O)-O- (CR5R6)n-R7, -(CR5R6)n-NR8R9, and -(CR5R6)n-C(=O)-NR8R9; each R3is selected from the group consisting of H, alkyl, Ar, -(CR5R6)n-Ar, -(CR5R6)n-O-C(=O)-R7, -(CR5R6)n- C(=O)-O-R7, - (CR5R6)n-O-C(=O)-O-R7, -(CR5R6)n-O-R7, -(CR5R6)n-O-[(CR5R6)n-O]m-R7, -(CR5R6)n-Ar-O- C(=O)-R7, -Ar-C(=O)-O-(CR5R6)n-R7, -(CR5R6)n-NR8R9, and -(CR5R6)n-C(=O)-NR8R9; and

[0184] each R4is selected from the group consisting of Ar, -(CR5R6)n-O-C(=O)-R7, -(CR5R6)n- C(=O)-O-R7, -(CR5R6)n-O-C(=O)-O-R7, -(CR5R6)n-O-R7, -(CR5R6)n-O-[(CR5R6)n-O]m-R7, - (CR5R6)n-Ar-O-C(=O)-R7, -Ar-C(=O)-O-(CR5R6)n-R7, -(CR5R6)n-NR8R9, and -(CR5R6)n-C(=O)- NR8R9;

[0185] (c) each R1is-(CR5R6)n-Ar; each R2is selected from the group consisting of H, alkyl, Ar, -(CR5R6)n-Ar, -(CR5R6)n-O-C(=O)-R7, -(CR5R6)n- C(=O)-O-R7, -(CR5R6)n-O-C(=O)-O- R7, -(CR5R6)n-O-R7, -(CR5R6)n-O-[(CR5R6)n-O]m-R7, -(CR5R6)n-Ar-O-C(=O)-R7, -Ar-C(=O)-O- (CR5R6)n-R7, -(CR5R6)n-NR8R9, and -(CR5R6)n-C(=O)-NR8R9; each R3is selected from the group consisting of H, alkyl, Ar, -(CR5R6)n-Ar, -(CR5R6)n-O-C(=O)-R7, -(CR5R6)n- C(=O)-O-R7, - (CR5R6)n-O-C(=O)-O-R7, -(CR5R6)n-O-R7, -(CR5R6)n-O-[(CR5R6)n-O]m-R7, -(CR5R6)n-Ar-O- C(=O)-R7, -Ar-C(=O)-O-(CR5R6)n-R7, -(CR5R6)n-NR8R9, and -(CR5R6)n-C(=O)-NR8R9; and each R4is selected from the group consisting of Ar, -(CR5R6)n-O-C(=O)-R7, -(CR5R6)n- C(=O)-O-R7, - (CR5R6)n-O-C(=O)-O-R7, -(CR5R6)n-O-R7, -(CR5R6)n-O-[(CR5R6)n-O]m-R7, -(CR5R6)n-Ar-O- C(=O)-R7, -Ar-C(=O)-O-(CR5R6)n-R7, -(CR5R6)n-NR8R9, and -(CR5R6)n-C(=O)-NR8R9; or

[0186] (d) each R1is selected from Ar, -(CR5R6)n-O-C(=O)-R7, -(CR5R6)n- C(=O)-O-R7, - (CR5R6)n-O-C(=O)-O-R7, -(CR5R6)n-O-R7, -(CR5R6)n-O-[(CR5R6)n-O]m-R7, -(CR5R6)n-Ar-O- C(=O)-R7, -Ar-C(=O)-O-(CR5R6)n-R7, -(CR5R6)n-NR8R9, and -(CR5R6)n-C(=O)-NR8R9; each R2is selected from the group consisting of H, alkyl, Ar, -(CR5R6)n-Ar, -(CR5R6)n-O-C(=O)-R7, - (CR5R6)n- C(=O)-O-R7, -(CR5R6)n-O-C(=O)-O-R7, -(CR5R6)n-O-R7, -(CR5R6)n-O-[(CR5R6)n-O]m- R7, -(CR5R6)n-Ar-O-C(=O)-R7, -Ar-C(=O)-O-(CR5R6)n-R7, -(CR5R6)n-NR8R9, and -(CR5R6)n- C(=O)-NR8R9;each R3is selected from the group consisting of H, alkyl, Ar, -(CR5R6Xi-Ar, - (CR5R6)n-O-C(=O)-R7, -(CR5R6)n- C(=O)-O-R7, -(CR5R6)n-O-C(=O)-O-R7, -(CR5R6)n-O-R7, - (CR5R6)n-O-[(CR5R6)n-O]m-R7, -(CR5R6)n-Ar-O-C(=O)-R7, -Ar-C(=O)-O-(CR5R6)n-R7, - (CR5R6)n-NR8R9, and -(CR5R6)n-C(=O)-NR8R9; and each R4is selected from the group consisting of H, alkyl, Ar, -(CR5R6)n-Ar, -(CR5R6)n-O-C(=O)-R7, -(CR5R6)n- C(=O)-O-R7, -(CR5R6)n-O- C(=O)-O-R7, -(CR5R6)n-O-R7, -(CR5R6)n-O-[(CR5R6)n-O]m-R7, -(CR5R6)n-Ar-O-C(=O)-R7, -Ar- C(=O)-O-(CR5R6)n-R7, -(CR5R6)n-NR8R9, and -(CR5R6)n-C(=O)-NR8R9;

[0187] wherein:

[0188] each n is an integer from 1 to 20;

[0189] each m is an integer from 1 to 20;

[0190] each R5and R6is independently selected from the group consisting of H, alkyl, and alkylaryl;

[0191] each R7is independently straight chain or branched alkyl;

[0192] each Ar is aryl, substituted aryl, heteroaryl or substituted heteroaryl;

[0193] each R8and R9are independently H or alkyl; and

[0194] each R3' and R4' are independently H or alkyl; and

[0195] pharmaceutically acceptable salts thereof.

[0196] In some embodiments, the compound is a compound of formula (Illa) and: R1is H; R2and R3are each selected from the group consisting of H, -(CR5R6)n-O-R7, -(CR5R6)n-Ar-O-C(=O)-R7, -(CR5R6)n-O-C(-O)-R7, -Ar-C(=O)-O-(CR5R6)n-R7, and -(CR5R6)n-O-C(=O)-O-R7; and R4is selected from the group consisting of -(CR5R6)n-O-R7, -(CR5R6)n-Ar-O-C(=O)-R7, -Ar-C(=O)-O- (CR5R6)n-R7, -(CR5R6)n-O-C(=O)-R7and -(CR5R6)n-O-C(=O)-O-R7; and pharmaceutically acceptable salts thereof.

[0197] In some embodiments, the compound is a compound of formula (Illa) and: R1is alkyl; R2and R3are each independently selected from the group consisting of H, alkyl, -(CR5R6)n-O-R7, -(CR5R6)n-Ar-O-C(=O)-R7, -(CR5R6)n-O-[(CR5R6)n-O]m-R7, -(CR5R6)n-O-C(=O)-R7and - (CR5R6)n-O-C(=O)-O-R7; and R4is selected from the group consisting of -(CR5R6)n-O-R7, - (CR5R6)n-Ar-O-C(=O)-R7, -(CR5R6)n-O-[(CR5R6)n-O]m-R7, -(CR5R6)n-O-C(=O)-R7and - (CR5R6)n-O-C(=O)-O-R7; and pharmaceutically acceptable salts thereof.

[0198] In some embodiments, the compound is a compound of formula (Illa) and: R1is selected from -(CR5R6)n-O-C(=O)-R7and -(CR5R6)n-O-C(=O)-O-R7; and R2R3, and R4are each independently selected from H, Ar, -(CR5R6)n-O-C(=O)-R7, and -(CR5R6)n-O-C(=O)-O-R7; and pharmaceutically acceptable salts thereof.

[0199] In some embodiments, the compound is a compound of formula (Illa) and: one of R1, R2, R3, or R4is H and the other three are each independently selected from the group consisting of: - (CR5R6)n-O-C(=O)-R7and -(CR5R6)n-O-C(=O)-O-R7; wherein R5and R6are each independently selected from the group consisting of H, C1-8straight-chain alkyl, and C1-8branched-chain alkyl; R7is C1-8straight-chain alkyl, and C1-8branched-chain alkyl; and pharmaceutically acceptable salts thereof.

[0200] In some embodiments, the compound is a compound of formula (Illa) and: R2is H; and R1, R3, and R4are each independently selected from the group consisting of: -(CR5R6)n-O-C(=O)- R7and -(CR5R6)n-O-C(=O)-O-R7; wherein R5and R6are each independently selected from the group consisting of H, C1-8straight-chain alkyl, and C1-8branched-chain alkyl; R7is C1-8straightchain alkyl or C1-8branched-chain alkyl; and pharmaceutically acceptable salts thereof.

[0201] In some embodiments, R5and R6are each H.

[0202] Representative embodiments of 2-PMPA prodrugs are disclosed in:

[0203] U.S. Patent No. 10,544,176 for Prodrugs of Prostate Specific Membrane Antigen (PSMA) Inhibitor, to Slusher et al., issued January 28, 2020;

[0204] U.S. Patent No. 9,988,407 for Prodrugs of Prostate Specific Membrane Antigen (PSMA) Inhibitor, to Slusher et al., issued June 5, 2018;

[0205] U.S. Patent Application Publication No. US 2020-0399298 Al for Prodrugs of Prostate Specific Membrane Antigen (PSMA) Inhibitor, to Slusher et al., published December 24, 2020, each of which is incorporated herein by reference in its entirety.

[0206] Other phosphonate-based GCPII inhibitors include GPI-5232, Jackson and Slusher, 2001, and VA-033, Ding et al., 2004:

[0207]

[0208] L-DOPA, D-DOPA, Caffeic acid, and Prodrugs Thereof

[0209] In some embodiments, the presently disclosed subject matter provides L-DOPA, D-DOPA, caffeic acid, and prodrugs thereof as GCPII inhibitors. Representative prodrugs of L-DOPA, D- DOPA, and caffeic acid are disclosed in International PCT Patent Application Publication No. WO2023064783 for DOPA and Caffeic Acid Analogs As Novel GCPII Inhibitors, to Rais et al., published April 20, 2023, which is incorporated herein by reference in its entirety.

[0210] More particularly, the presently disclosed subject matter provides prodrugs of L-DOPA, D-DOPA, and caffeic acid as compounds of formula (IV):

[0211]

[0212] wherein:

[0213] indicates that the bond can be a single or a double bond;

[0214] R1is:

[0215] -OR5, wherein R5is selected from the group consisting of H, C1-C8alkyl, and -O-(CH2)n- R6, wherein n is an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, and 8 and R6is substituted or unsubstituted aryl or heteroaryl; or

[0216] -NR7R8, wherein R7and R8are each independently selected from the group consisting of H, C1-C4alkyl, C3-C6cycloalkyl, C1-C8alkoxyl, unsubstituted or substituted aryl or heteroaryl, -(CH2)m-R9, wherein R9is -OR10or CHX2, wherein R10is H or C1-C4alkyl, and each X is halogen, and -(CH2)m-CH(NH2)(COOH), wherein each m is independently an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, and 8;

[0217] R2is H or -NR11R12, wherein R11and R12are each independently selected from the group consisting of H, C1-C4alkyl, and -C(=O)-R13, wherein R13is C1-C4alkyl or

[0218] -C(NH2)-(CH2)p-R14, wherein R14is C1-C4alkyl or -NR15R16, wherein R15and R16are each H or C1-C4alkyl, and p is an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, and 8;

[0219] R3and R4are each independently H or -C(=O)-R17, wherein R17is C1-C8alkyl or

[0220] -(CH2)t-O-C(=O)-O-R18, wherein R18is C1-C8alkyl, and t is an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, and 8; and

[0221] stereoisomers and pharmaceutically acceptable salts thereof.

[0222] In certain embodiments, R1is -OR5, and R5is selected from the group consisting of H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, isopentyl, neopentyl, n-hexyl, sec-hexyl, n-heptyl, and n-octyl.

[0223] In certain embodiments, R1is -OR5, and R5is H or -O-(CH2)n-R6, wherein R6is substituted or un substituted phenyl.

[0224] In certain embodiments, R1is -NR7R8, and R7is H or C1-C4alkyl and R8is selected from the group consisting of H, C1-C4alkyl, C3-C6cycloalkyl, unsubstituted or substituted phenyl, - (CH2)m-R9, wherein R9is -OR10or CHX2, wherein R10is H or C1-C4alkyl, and each X is halogen, and -(CH2)m-CH(NH2)(COOH), wherein each m is independently an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, and 8.

[0225] In certain embodiments, R2is -NR11R12, wherein R11is H and R12is H or -C(=O)-R13, wherein R13is C1-C4alkyl or -C(NH2)-(CH2)p-R14, wherein R14is C1-C4alkyl or

[0226] -NR15R16, wherein R15and R16are each H or C1-C4alkyl, and p is an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, and 8.

[0227] In certain embodiments, R3and R4are each H.

[0228] In certain embodiments, if R1is -OR5, then R5cannot be H.

[0229] In certain embodiments, if R1is -OR5, then R3, R4, and R5cannot all be H.[00230JIn certain embodiments, R3and R4are each independently selected from the group consisting of -C(=O)-CH3, -C(=O)-C(CH3)3, and -CH2-O-C(-O)-O-CH(CH3)2.

[0231] In particular embodiments, the compound of formula (IV) is selected from the group consisting of:

[0238]

[0239] Phosphinate -based GCPII Inhibitors

[0240] Representative phosphinate-based GCPII inhibitors include, but are not limited to:

[0241] 2-[[methylhydroxyphosphinyl]methyl]pentanedioic acid;

[0242] 2-[[ethylhydroxyphosphinyl]methyl]pentanedioic acid;

[0243] 2-[[propylhydroxyphosphinyl]methyl]pentanedioic acid;

[0244] 2-[[butylhydroxyphosphinyl]methyl]pentanedioic acid;

[0245] 2-[[cyclohcxylhydroxyphosphinyl]mcthyl]pcntancdioic acid;

[0246] 2-[[phenylhydroxyphosphinyl]methyl]pentanedioic acid;

[0247] 2-[[(phcnylmcthyl)hydroxyphosphinyl]mcthyl]pcntancdioic acid;

[0248] 2-[[((2-phenylethyl)methyl)hydroxyphosphinyl]methyl]pentanedioic acid;

[0249] 2-[[((3-phenylpropyl)methyl)hydroxyphosphinyl]methyl]pentanedioic acid;

[0250] 2-[[((3-phenylbutyl)methyl)hydroxyphosphinyl]methyl]pentanedioic acid;

[0251] 2-[[((2-phenylbutyl)methyl)hydroxyphosphinyl]methyl]pentanedioic acid;

[0252] 2- [ [(4-pheny Ibuty l)hy droxypho sphiny 1] methyl] pentanedioic acid;

[0253] 2-[[(aminomethyl)hydroxyphosphinyl]methyl]pentanedioic acid;

[0254] 7-(L-2-amino-2-carboxyethylthio)-2-(2,2-dimethylcyclopropanecarboxamide)-2- heptenoic acid; 2-(phosphonomethyl)pentanedioic acid;

[0255] N-[methylhydroxyphosphinyl]glutamic acid;

[0256] N-[ethylhydroxyphosphinyl]glutamic acid;

[0257] N-[propylhydroxyphosphinyl]glutamic acid;

[0258] N-[butylhydroxyphosphinyl]glutamic acid;

[0259] N-[phenylhydroxyphosphinyl]glutamic acid; and

[0260] N-[(phenylmethyl)hydroxyphosphinyl]glutamic acid.

[0261] See U.S. Patent No. 11,167,049, for Organ protection in PSMA-targeted radionuclide therapy of prostate cancer, to Babich et al., issued Nov. 9, 2021, which is incorporated herein by reference in its entirety.

[0262] Pho sphoramidate-based GCPII Inhibitors

[0263] Phosphoramidate-based GCPII inhibitors include compounds of formula (V):

[0264] (V).

[0265] Representative phosphoramidate-based GCPII inhibitors are disclosed in Ferraris et al., 2012, and include compounds of formula (V’);

[0266]

[0267] wherein R is H or C1-C4alkyl, and R’ is benzyl; or a compound of formula (V”):

[0268]

[0269] wherein R is selected from H, 4-fluorobenzoyl, and 6-(fluorescein-5- carboxamido)hexanoyl.

[0270] Thiol -based GCPII Inhibitors

[0271] Representative thiol-based GCPII inhibitors include 3-(2-mercaptoethyl)biphenyl-2,3- dicarboxylic acid (E2072) and GPI-5693:

[0272]

[0273] See Wozniak et al., 2012b; Slusher et al., 2001. Other thiol-based are provided in Bafinka et al., 2012, and International Patent Application No. W02002057222 for Thiol-Based NAALADASE Inhibitors, to Tsukamoto et al., published July 25, 2002, which is incorporated herein by reference in its entirety.

[0274] Urea-based GCPII Inhibitors

[0275] Urea-based GCPII inhibitors include MIP-1555, MIP-1519, MIP-1545, MIP-1427, MIP- 1428, MIP-1379, MIP-1072, MIP-1095, MIP-1558, MIP-1405, and MIP-1404. See U.S. PatentNo. 11,167,049, for Organ protection in PSMA-targeted radionuclide therapy of prostate cancer, to Babich et al., issued Nov. 9, 2021, which is incorporated herein by reference in its entirety.

[0276] Other urea-based GCPII inhibitors include PSMA I&T, Weineisen et al., 2015, PSMA- 617, Benesova et al., 2015, PSMA-11, Eder et al., 2012, DCIBzL, Chen et al., 2008,18F-DCFPyl, Chen et al., 2011, ZJ 38, GCPII-IN-1, and JB-352, Knedlrk et al., 2017:

[0278]

[0279] Dendrimer Conjugates of 2-PMPA, 2-MPPA, and other GCP II Inhibitors

[0280] In some embodiments, the dendrimers are in the form of dendrimer nanoparticles comprising poly(amidoamine) (PAMAM) hydroxyl-terminated dendrimers covalently linked, for example to 2-PMPA, 2-MPPA, or another GCPII inhibitor. Representative dendrimer compositions suitable for use with the presently disclosed methods are disclosed in International PCT Patent Application Publication No. WO2016025745 for Dendrimer Compositions and use in Treatment of Neurological and CNS Disorders, to Rangaramanujam et al., published February 18, 2016, which is incorporated herein in its entirety.

[0281] In particular embodiments, the dendrimer nanoparticles include one or more ethylene diamine-core PAMAM hydroxyl-terminated generation-4 through generation-10 (e.g., >G4-OH) dendrimers covalently linked to 2-PMPA.

[0282] As used herein, the term “dendrimer” includes, but is not limited to, a molecular architecture having an interior core, interior layers (or “generations”) of repeating units regularly attached to the interior core, and an exterior surface of terminal groups attached to the outermost generation. Dendrimers suitable for use with the presently disclosed methods include, but are not limited to, polyamidoamine (PAMAM), polypropyiamine (POPAM), poly(propylene imine) (PPI), polyethylenimine, polylysine, polyester, iptycene, aliphatic poly(ether), and / or aromatic poly ether dendrimers. Each dendrimer of the dendrimer complex may be of similar or different chemical nature than the other dendrimers (e.g., the first dendrimer may include a PAMAM dendrimer, while the second dendrimer may comprise a POPAM dendrimer). In some embodiments, the first or second dendrimer may further include an additional agent. In some embodiments, a multiarm PEG polymer can include a polyethylene glycol having at least two branches bearing sulfhydryl or thiopyridine terminal groups; however, embodiments disclosed herein are not limited to this class and PEG polymers hearing other terminal groups, such as succinimidyl or maleimide terminal groups, can be used. In particular embodiments, PEG polymers in the molecular weight 10 kDa to 80 kDa can be used.

[0283] In certain embodiments, the dendrimer complex can include multiple dendrimers. For example, the dendrimer complex can include a third dendrimer; wherein the third-dendrimer iscomplexed with at least one other dendrimer. Further, a third agent can be complexed with the third dendrimer. In another embodiment, the first and second dendrimers are each complexed to a third dendrimer, wherein the first and second dendrimers are PAMAM dendrimers and the third dendrimer is a POPAM dendrimer. Additional dendrimers also can be incorporated. When multiple dendrimers are used, multiple agents also can be incorporated. This characteristic is not limited by the number of dendrimers complexed to one another.

[0284] As used herein, the term “PAMAM dendrimer” refers to a poly(amidoamine) dendrimer, which may contain different cores, with amidoamine building blocks. The method for making them is known to those of skill In the art and generally, involves a two-step iterative reaction sequence that produces concentric shells (i.e., “generations”) of dendritic β-alanine units around a central interior core. This PAMAM core-shell architecture grows linearly in diameter as a function of added shells (generations). Meanwhile, the surface groups amplify exponentially at each generation according to dendritic-branching mathematics. Such dendrimers are available in generations GO - GIO with 5 different core types and 10 functional surface groups.

[0285] In certain embodiments, the PAMAM dendrimers can have carboxylic, amine and hydroxyl terminal groups and can be any generation of dendrimers including, but not limited to, generation 1 PAMAM dendrimers, generation 2 PAMAM dendrimers, generation 3 PAMAM dendrimers, generation 4 PAMAM dendrimers, generation 5 PAMAM dendrimers, generation 6 PAMAM dendrimers, generation 7 PAMAM dendrimers, generation 8 PAMAM dendrimers, generation 9 PAMAM dendrimers, or generation 10 PAMAM dendrimers. In particular embodiments, the PAMAM dendrimers can be generation 4 dendrimers, or more, with hydroxyl groups attached to their functional surface groups.

[0286] Representative dendrimers suitable for use with the presently disclosed methods are disclosed in International PCT Patent Application Publication No. W02009 / 046446 for Dendrimers for Sustained Release of Compounds, to Kannan et al., published April 9, 2009, which is incorporated herein by reference in its entirety.

[0287] Dendrimer complexes can be formed by covalently bonding or otherwise attaching, e.g., via intermolecularly dispersion or encapsulation, a therapeutically active agent, e.g., 2-PMPA, to a dendrimer or multiarm PEG. The attachment can occur via an appropriate spacer that provides a disulfide bridge between the agent and the dendrimer. The dendrimer complexes are capable ofrapid release of the agent in vivo by thiol exchange reactions, under the reduced conditions found in a body.

[0288] The term “spacers” as used herein is intended to include compositions used for linking a therapeutically active agent to the dendrimer. The spacer can be either a single chemical entity or two or more chemical entities linked together to bridge the polymer and the therapeutic agent or imaging agent. The spacers can include any small chemical entity, peptide or polymers having sulfhydryl, thiopyridine, succinimidyl, maleimide, vinylsulfone, and carbonate terminal groups.

[0289] In certain embodiments, the spacer can comprise thiopyridine terminated compounds including, but not limited to, dithiodipyridine, N- succinimidyl 3-(2-pyridyldithio)-propionate (SPDP), succinimidyl 6-(3-[2-pyridyldithio]-propionamido)hexanoate LC-SPDP, or Sulfo-LC- SPDP. The spacer also can include peptides wherein the peptides are linear- or cyclic having sulfhydryl groups, such as glutathione, homocysteine, cysteine and its derivatives, arg-gly-asp-cys (RGDC), cyclo(Arg-Gly-Asp-d-Phe-Cys) (c(RGDfC)), cyclo(Arg-Gly-Asp-D-Tyr-Cys), cyelo(Arg-Ala-Asp-d-Tyr-Cys). The spacer can be a mercapto acid derivative such as 3-mercapto propionic acid, mercapto acetic acid, 4-mercapto butyric acid, thiolan-2-one, 6-mercaptohexanoic acid, 5-mercapto valeric acid and other mercapto derivatives such as 2-mercaptoethanol and 2- mercaptoethylamine. The spacer can be thio s alicyclic acid and its derivatives including (4- succinimidyloxycarbonyl-methyl-a-2-pyridylthio)toluene and (3-[2-pyridithio]propionyl hydrazide. The spacer can have maleimide terminal groups wherein the spacer comprises polymer or small chemical entity, such as bis-maleimido diethylene glycol and bis-maleimido triethylene glycol, bismaleimidoethane, bismaleimidohexane. The spacer can comprise a vinylsulfone, such as 1,6-hexane-bis-vinylsulfone. The spacer can comprise thioglycosides, such as thioglucose. The spacer can be a reduced protein, such as bovine serum albumin and human serum albumin, or any thiol terminated compound capable of forming disulfide bonds. The spacer can include polyethylene glycol having maleimide, succinimidyl and thiol terminal groups.

[0290] Other GCPII Inhibitors

[0291] Other representative GCPII inhibitors include quisqualate and β-citryl-L-glutamate;

[0292]

[0293] See Knedlik et al., 2017.

[0294] In some embodiments, the GCPII inhibitor includes:

[0295] (S)-2-((N-((S)-l,2-dicarboxyethyl)sulfamoyl)amino)pentanedioic acid:

[0296]

[0297] (S)-2-((((S)-5-(4-bromo-2-fluorobenzamido)-l- carboxypcntyl)carbamoyl)oxy)pcntancdioic acid:

[0299] (5)-2-((5)- 1 -carboxy-3-methylbutylcarbamoyloxy )pentanedioic acid:

[0301] In particular embodiments, the GCPII inhibitor is 2-(phosphonomethyl)-pentanedioic acid (2-PMPA).

[0302] In certain embodiments, the stress hormone is selected from aldosterone, corticosterone, and a combination thereof. For example, aldosterone is a steroid hormone made by the adrenal cortex (i.e., the outer layer of the adrenal gland). It helps control the balance of water and salts in the kidney by keeping sodium in and releasing potassium from the body. Too much aldosterone, however, can cause high blood pressure and a build-up of fluid in body tissues.

[0303] Likewise, corticosterone is a major stress hormone produced in the cortex of the adrenal gland. Chronically elevated corticosterone levels activate the chronic stress-response network, and, as a result, impact various processes involved in coping with stress, including physiologicalconditions, such as increased blood glucose levels, and psychological conditions, including depression and anxiety. Other stress-related hormones include, but arc not limited to, catecholamines, such as adrenaline and norepinephrine, vasopressin, and growth hormone.

[0304] In certain embodiments, administering the therapeutically effective amount of the GCPII inhibitor comprises blocking a stress-induced increase in plasma levels of the stress-induced hormone. In particular embodiments, the blocking of the stress-induced increase in plasma levels of the stress-induced hormone has no effect on a basal level of the stress-induced hormone.

[0305] In other embodiments, the presently disclosed subject matter provides a method for treating a disease, disorder, or condition in a subject in need of treatment thereof, the method comprising reducing stress-induced hormone production in the subject by administering a therapeutically effective amount of a glutamate carboxypeptidase II (GCPII) inhibitor to the subject.

[0306] In certain embodiments, the disease, disorder, or condition comprises a stress-related psychiatric disorder. In particular embodiments, the stress-related psychiatric disorder is selected from depression, anxiety, bipolar disorder, and obsessive-compulsive disorder.

[0307] In certain embodiments, the disease, disorder, or condition comprises a neurodegenerative disease. In particular embodiments, the neurodegenerative disease is selected from Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, multiple sclerosis, muscular dystrophy, and Huntington's disease. In more particular embodiments, the method comprises slowing onset or progression of Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, multiple sclerosis, muscular dystrophy, and Huntington's disease.

[0308] In certain embodiments, the disease, disorder, or condition comprises a cardiovascular disease. In certain embodiments, the method comprises reducing a risk of a heart attack or a stroke. In certain embodiments, the method comprises lowering one or more clinical conditions regulated by plasma stress hormones. In particular embodiments, the one more clinical conditions is selected from blood cholesterol levels, triglyceride levels, blood sugar levels, blood pressure, and arterial stiffness.

[0309] In certain embodiments, the disease, disorder, or condition comprises Cushing syndrome.

[0310] In certain embodiments, the disease, disorder, or condition is associated with an elevated level of GCPII in the subject in need of treatment compared to a control subject not afflicted with the condition, disease, or disorder. As used herein, the term “elevated,” as in “an elevated level of GCPII,” refers to a level of GCPII in a subject having or suspected of having a disease, disorder,or condition associated with an elevated level of GCPII compared to a level of GCPII in a normal subject, i.c., a subject who docs not have or is not suspected of having a disease, disorder, or condition associated with an elevated level of GCPII, such as an increase of approximately 50%, 100%, 200%, 300%, 400%, 500%, or more.

[0311] In some embodiments, performing the presently disclosed method results in inhibiting GCPII activity in a subject. As used herein, the term “inhibit” means to decrease or diminish the GCPII activity found in a subject, e.g., 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 80%, 85%, 90%, 95%, 985, 99%, or 100% of the GCPII activity compared to an untreated control subject or a subject without the disease or disorder. The term “inhibit” also may mean to decrease, suppress, attenuate, diminish, arrest, or stabilize the development or progression of a disease, disorder, or condition.

[0312] As used herein, the term “treating” can include reversing, alleviating, inhibiting the progression of, preventing, or reducing the likelihood of the disease, disorder, or condition to which such term applies, or one or more symptoms or manifestations of such disease, disorder, or condition. Preventing refers to causing a disease, disorder, condition, or symptom or manifestation of such, or worsening of the severity of such, not to occur. Accordingly, the presently disclosed compounds can be administered prophylactically to prevent or reduce the incidence or recurrence of the disease, disorder, or condition.

[0313] The “subject” treated by the presently disclosed methods in their many embodiments is desirably a human subject, although it is to be understood that the methods described herein are effective with respect to all vertebrate species, which are intended to be included in the term “subject.” Accordingly, a “subject” can include a human subject for medical purposes, such as for the treatment of an existing condition or disease or the prophylactic treatment for preventing the onset of a condition or disease, or an animal subject for medical, veterinary purposes, or developmental purposes. Suitable animal subjects include mammals including, but not limited to, primates, e.g., humans, monkeys, apes, and the like; bovines, e.g., cattle, oxen, and the like; ovines, e.g., sheep and the like; caprines, e.g., goats and the like; porcines, e.g., pigs, hogs, and the like; equines, e.g., horses, donkeys, zebras, and the like; felines, including wild and domestic cats; canines, including dogs; lagomorphs, including rabbits, hares, and the like; and rodents, including mice, rats, and the like. An animal may be a transgenic animal. In some embodiments, the subject is a human including, but not limited to, fetal, neonatal, infant, juvenile, and adult subjects. Further,a “subject” can include a patient afflicted with or suspected of being afflicted with a condition or disease. Thus, the terms “subject” and “patient” arc used interchangeably herein. The term “subject” also refers to an organism, tissue, cell, or collection of cells from a subject.

[0314] In general, a “therapeutically effective amount” of a therapeutic agent refers to the amount of the agent necessary to elicit the desired biological response. As will be appreciated by those of ordinary skill in the art, the effective amount of an agent may vary depending on such factors as the desired biological endpoint, the agent to be delivered, the composition of the pharmaceutical composition, the target tissue or cell, and the like. In some embodiments, the term “therapeutically effective amount” refers to an amount sufficient to reduce or ameliorate the severity, duration, progression, or onset of a disease, disorder, or condition, or one or more symptoms thereof; prevent the advancement of a disease, disorder, or condition, cause the regression of a disease, disorder, or condition; prevent the recurrence, development, onset or progression of a symptom associated with a disease, disorder, or condition, or enhance or improve the prophylactic or therapeutic effect(s) of another therapy.

[0315] The term “combination” is used in its broadest sense and means that a subject is administered at least two agents, more particularly a compound disclosed herein and at least one other therapeutic agent. More particularly, the term “in combination” refers to the concomitant administration of two (or more) active agents for the treatment of a, e.g., single disease state. As used herein, the active agents may be combined and administered in a single dosage form, may be administered as separate dosage forms at the same time, or may be administered as separate dosage forms that are administered alternately or sequentially on the same or separate days. In one embodiment of the presently disclosed subject matter, the active agents are combined and administered in a single dosage form. In another embodiment, the active agents are administered in separate dosage forms (e.g., wherein it is desirable to vary the amount of one but not the other). The single dosage form may include additional active agents for the treatment of the disease state.

[0316] Further, the compounds disclosed herein can be administered alone or in combination with adjuvants that enhance stability of the compounds, alone or in combination with one or more therapeutic agents, facilitate administration of pharmaceutical compositions containing them in certain embodiments, provide increased dissolution or dispersion, increase inhibitory activity, provide adjunct therapy, and the like, including other active ingredients. Advantageously, suchcombination therapies utilize lower dosages of the conventional therapeutics, thus avoiding possible toxicity and adverse side effects incurred when those agents arc used as monotherapies.

[0317] The timing of administration of a compound disclosed herein and at least one additional therapeutic agent can be varied so long as the beneficial effects of the combination of these agents are achieved. Accordingly, the phrase “in combination with” refers to the administration of a compound described herein and at least one additional therapeutic agent either simultaneously, sequentially, or a combination thereof. Therefore, a subject administered a combination of a compound described herein and at least one additional therapeutic agent can receive a compound and at least one additional therapeutic agent at the same time (i.e., simultaneously) or at different times (i.e., sequentially, in either order, on the same day or on different days), so long as the effect of the combination of both agents is achieved in the subject.

[0318] When administered sequentially, the agents can be administered within 1, 5, 10, 30, 60, 120, 180, 240 minutes or longer of one another. In other embodiments, agents administered sequentially, can be administered within 1, 5, 10, 15, 20 or more days of one another. Where the compound described herein and at least one additional therapeutic agent are administered simultaneously, they can be administered to the subject as separate pharmaceutical compositions, each comprising either a compound or at least one additional therapeutic agent, or they can be administered to a subject as a single pharmaceutical composition comprising both agents.

[0319] When administered in combination, the effective concentration of each of the agents to elicit a particular biological response may be less than the effective concentration of each agent when administered alone, thereby allowing a reduction in the dose of one or more of the agents relative to the dose that would be needed if the agent was administered as a single agent. The effects of multiple agents may, but need not be, additive or synergistic. The agents may be administered multiple times.

[0320] In some embodiments, when administered in combination, the two or more agents can have a synergistic effect. As used herein, the terms “synergy,” “synergistic,” “synergistically” and derivations thereof, such as in a “synergistic effect” or a “synergistic combination” or a “synergistic composition” refer to circumstances under which the biological activity of a combination of a compound described herein and at least one additional therapeutic agent is greater than the sum of the biological activities of the respective agents when administered individually.

[0321] Synergy can be expressed in terms of a “Synergy Index (SI),” which generally can be determined by the method described by F. C. Kull ct al., Applied Microbiology 9, 538 (1961), from the ratio determined by:

[0322] Qa / QA+ Qb / QB= Synergy Index (SI)

[0323] wherein:

[0324] QAis the concentration of a component A, acting alone, which produced an end point in relation to component A;

[0325] Qais the concentration of component A, in a mixture, which produced an end point;

[0326] QBis the concentration of a component B, acting alone, which produced an end point in relation to component B; and

[0327] Qbis the concentration of component B, in a mixture, which produced an end point.

[0328] Generally, when the sum of Qa / QAand Qb / QBis greater than one, antagonism is indicated. When the sum is equal to one, additivity is indicated. When the sum is less than one, synergism is demonstrated. The lower the SI, the greater the synergy shown by that particular mixture. Thus, a “synergistic combination” has an activity higher that what can be expected based on the observed activities of the individual components when used alone. Further, a “synergistically effective amount” of a component refers to the amount of the component necessary to elicit a synergistic effect in, for example, another therapeutic agent present in the composition.

[0329] Depending on the specific conditions being treated, the “agent(s)” may be formulated into liquid or solid dosage forms and administered systemically or locally. The agents may be delivered, for example, in a timed- or sustained-slow release form as is known to those skilled in the art. Techniques for formulation and administration may be found in Remington: The Science and Practice of Pharmacy (20th ed.) Lippincott, Williams & Wilkins (2000). Suitable routes may include oral, buccal, by inhalation spray, sublingual, rectal, transdermal, vaginal, transmucosal, nasal or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intra-articular, intra- sternal, intra-synovial, intra-hepatic, intralesional, intracranial, intraperitoneal, intranasal, or intraocular injections or other modes of delivery.

[0330] For injection, the agents of the disclosure may be formulated and diluted in aqueous solutions, such as in physiologically compatible buffers such as Hank’s solution, Ringer’s solution, or physiological saline buffer. For such transmucosal administration, penetrants appropriate to thebarrier to be permeated are used in the formulation. Such penetrants are generally known in the art.

[0331] Use of pharmaceutically acceptable inert carriers to formulate the compounds herein disclosed for the practice of the disclosure into dosages suitable for systemic administration is within the scope of the disclosure. With proper choice of carrier and suitable manufacturing practice, the compositions of the present disclosure, in particular, those formulated as solutions, may be administered parenterally, such as by intravenous injection. The compounds can be formulated readily using pharmaceutically acceptable carriers well known in the art into dosages suitable for oral administration. Such carriers enable the compounds of the disclosure to be formulated as tablets, pills, capsules, liquids, gels, syrups, slurries, suspensions, and the like, for oral ingestion by a subject (e.g., patient) to be treated.

[0332] For nasal or inhalation delivery, the agents of the disclosure also may be formulated by methods known to those of skill in the art, and may include, for example, but not limited to, examples of solubilizing, diluting, or dispersing substances, such as saline; preservatives, such as benzyl alcohol; absorption promoters; and fluorocarbons.

[0333] In particular embodiments, the compound disclosed herein is administered intranasally in a form selected from the group consisting of a nasal spray, a nasal drop, a powder, a granule, a cachet, a tablet, an aerosol, a paste, a cream, a gel, an ointment, a salve, a foam, a paste, a lotion, a cream, an oil suspension, an emulsion, a solution, a patch, and a stick. As used herein, the term administrating via an "intranasal route" refers to administering by way of the nasal structures.

[0334] Pharmaceutical compositions suitable for use in the present disclosure include compositions wherein the active ingredients are contained in an effective amount to achieve its intended purpose. Determination of the effective amounts is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein. Generally, the compounds according to the disclosure are effective over a wide dosage range. For example, in the treatment of adult humans, dosages from 0.01 to 1000 mg, from 0.5 to 100 mg, from 1 to 50 mg per day, and from 5 to 40 mg per day are examples of dosages that may be used. A non-limiting dosage is 10 to 30 mg per day. The exact dosage will depend upon the route of administration, the form in which the compound is administered, the subject to be treated, the body weight of the subject to be treated, the bioavailability of the compound(s), the adsorption, distribution,metabolism, and excretion (ADME) toxicity of the compound(s), and the preference and experience of the attending physician.

[0335] In addition to the active ingredients, these pharmaceutical compositions may contain suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. The preparations formulated for oral administration may be in the form of tablets, dragees, capsules, or solutions.

[0336] Pharmaceutical preparations for oral use can be obtained by combining the active compounds with solid excipients, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethyl-cellulose (CMC), and / or polyvinylpyrrolidone (PVP: povidone). If desired, disintegrating agents may be added, such as the cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

[0337] Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol (PEG), and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dye-stuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

[0338] Pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin, and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols (PEGs). In addition, stabilizers may be added.

[0339] Further, one of ordinary skill in the art will recognize that the presently disclosed compounds, and pharmaceutical compositions thereof, include pharmaceutically acceptable salts. Pharmaceutically acceptable salts are generally well known to those of ordinary skill in the art,and include salts of active compounds that can be prepared with relatively nontoxic acids or bases, depending on the particular substituent moictics found on the compounds described herein. The parent form of the compound can differ from the various salt forms in certain physical properties, such as solubility, and the like.

[0340] When compounds of the present disclosure contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent or by ion exchange, whereby one basic counterion (base) in an ionic complex is substituted for another. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, magnesium, and the like.

[0341] When compounds of the present disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent or by ion exchange, whereby one acidic counterion (acid) in an ionic complex is substituted for another. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids, organic acids, and amino acids. See, for example, Berge et al, “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19). Compounds containing both basic and acidic functionalities allow such compounds to be converted into either base or acid addition salts.

[0342] Accordingly, pharmaceutically acceptable salts suitable for use with the presently disclosed subject matter include, by way of example but not limitation, acetate, arginate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, monohydrogencarbonate, citrate, edetate, edisylate, estolate, esylate, fumarate, galactonate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydriodic, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, isobutyrate, lactate, lactobionate, malate, maleate, malonate, mandelate, mesylate, methanesulfonate, mucate, napsylate, nitrate, pamoate (embonate), pantothenate, phosphate, phthalate, diphosphate, monohydrogen phosphate, dihydrogen phosphate, polygalacturonate, propionate, salicylate, stearate, subacetate, suberate, succinate, sulfate, monohydrogensulfate, tannate, tartrate, including (+)-tartrates, (-)-tartrates, and mixtures thereof including racemic mixtures, teoclate, p- toluenesulfonate and trifluoroacetate. Other pharmaceutically acceptable salts may be found in,for example, Remington: The Science and Practice of Pharmacy (20th ed.) Lippincott, Williams & Wilkins (2000).

[0343] Unless otherwise noted, the chemical definitions provided immediately herein below are intended to comply with IUPAC. Compendium of Chemical Terminology, 2nd ed. (the "Gold Book"). Compiled by A. D. McNaught and A. Wilkinson. Blackwell Scientific Publications, Oxford (1997).

[0344] The term “hydrocarbon” as used herein, refers to any chemical group comprising hydrogen and carbon. A hydrocarbon group may be substituted or unsubstituted. As would be known to one of ordinary skill in the art, all valencies must be satisfied in making any substitutions. The hydrocarbon may be unsaturated, saturated, branched, unbranched, cyclic, polycyclic, or heterocyclic.

[0345] The term “aliphatic” or “aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “carbocyclyl”, “cycloaliphatic”, or “cycloalkyl”), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-4 alipatic carbon atoms. In some embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, “cycloaliphatic” (or “carbocyclyl” or “cycloalkyl”) refers to a monocyclic C3-C7 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0346] The term “alkane” refers to acyclic branched or unbranched hydrocarbons having the general formula CnH2n+2, and therefore consisting entirely of hydrogen atoms and saturated carbon atoms.

[0347] The term “alkyl” refers to a univalent group derived from an alkane by removal of a hydrogen atom from any carbon atom and having the chemical formula of -CnH2n+1. The groups derived by removal of a hydrogen atom from a terminal carbon atom of unbranched alkanes form a subclass of normal alkyl (n-alkyl) groups H(CH2)n. The groups RCH2, R2CH (RH), and R3C (R H) are primary, secondary and tertiary alkyl groups, respectively.

[0348] An alkyl can be a straightchain (i.e., unbranched) or branched acyclic hydrocarbon having the number of carbon atoms designated (i.e., C1-10means one to ten carbons, including 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 carbons). In particular embodiments, the term “alkyl” refers to C1-20inclusive, including 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 carbons. In other embodiments, the alkyl can be a C1-C4alkyl, including 1, 2, 3, and 4 carbons. In yet other embodiments, the alkyl can be a C1-C6alkyl, including 1, 2, 3, 4, 5, and 6 carbons. In even yet other embodiments, the alkyl can be a C1-C8alkyl, including 1, 2, 3, 4, 5, 6, 7, and 8 carbons.

[0349] ‘ ‘Lower alkyl” refers to an alkyl group having 1 to about 8 carbon atoms (i.e., a C1-8alkyl), e.g., 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. “Higher alkyl” refers to an alkyl group having about 10 to about 20 carbon atoms, e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms. In certain embodiments, “alkyl” refers to straight-chain alkyls. In other embodiments, “alkyl” refers to branched alkyls. In certain other embodiments, “alkyl” refers to straight-chain and / or branched alkyls. “Branched” refers to an alkyl group in which a lower alkyl group, such as methyl, ethyl or propyl, is attached to a linear alkyl chain.

[0350] Representative alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec -butyl, tert-butyl, n-pentyl, sec-pentyl, isopentyl, neopentyl, n- hexyl, sec-hexyl, n-heptyl, n-octyl, n-decyl, n-undecyl, and dodecyl.

[0351] Alkyl groups can optionally be substituted (a “substituted alkyl”) with one or more substituents, which can be the same or different. Such substituent groups include, but are not limited to, alkyl, substituted alkyl, cycloalkyl, halogen, acyl, carboxyl, oxo, aryl, substituted aryl, alkoxyl, hydroxyl, nitro, amino, alkylamino, dialkylamino, sulfate, cyano, and mercapto.

[0352] The term “heteroalkyl,” by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain having from 1 to 20 carbon atoms or heteroatoms consisting of at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si and S, and wherein the nitrogen, phosphorus, and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. Theheteroatom(s) O, N, P and S and Si may be placed at any interior position of the heteroalkyl group or at the position at which alkyl group is attached to the remainder of the molecule. Examples include, but are not limited to, -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, - CH2-S-CH2-CH3, -CH2-CH2-S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, - CH2-CH=N-OCH3, -CH=CH-N(CH3)- CH3, O-CH3, -O-CH2-CH3, and -CN. Up to two or three heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3and -CH2-O-Si(CH3)3.

[0353] The term “cycloalkane” refers to saturated monocyclic hydrocarbons (with or without side chains), e.g., cyclobutane. Unsaturated monocyclic hydrocarbons having one endocyclic double or one triple bond are called cycloalkenes and cycloalkynes, respectively. Those having more than one such multiple bond are cycloalkadienes, cycloalkatrienes, and the like. The inclusive terms for any cyclic hydrocarbons having any number of such multiple bonds are cyclic olefins or cyclic acetylenes.

[0354] The term “cycloalkyl” refer to a univalent group derived from a cycloalkane by removal of a hydrogen atom from a ring carbon atom. Cycloalkyls can be a mono- or multicyclic ring system of about 3 to about 10 carbon atoms, e.g., 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. The cycloalkyl group also can be optionally substituted with a substituent group provided hereinabove for alkyl groups. Representative monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Multicyclic cycloalkyl rings include adamantyl, octahydronaphthyl, decalin, camphor, camphane, and noradamantyl, and fused ring systems, such as dihydro- and tetrahydronaphthalene, and the like.

[0355] The term “cycloalkylalkyl” as used herein, refers to a cycloalkyl group, which is attached to the parent molecular moiety through an alkylene moiety, also as defined above, e.g., a C1-20alkylene moiety. Examples of cycloalkylalkyl groups include cyclopropylmethyl and cyclopentylethyl .

[0356] The terms “cycloheteroalkyl” and “heterocycloalkyl” (or more generally “heterocyclic”) are used interchangeably and refer to an unsaturated ring system, such as a 3- to 10-member substituted or unsubstituted cycloalkyl ring system, including one or more heteroatoms, which can be the same or different, and are selected from the group consisting of nitrogen (N), oxygen (O), sulfur (S), phosphorus (P), and silicon (Si), in which the nitrogen, sulfur, and phosphorus heteroatoms may be oxidized and the nitrogen heteroatom may be quatemized. The cyclohetero alkyl ring can be optionally fused to or otherwise attached to other cycloheteroalkylrings and / or non-aromatic hydrocarbon rings. Representative cycloheteroalkyl ring systems include, but are not limited to pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, indolinyl, quinuclidinyl, morpholinyl, thiomorpholinyl, thiadiazinanyl, tetrahydrofuranyl, and the like.

[0357] The terms “cycloalkylene” and “heterocycloalkylene” refer to the divalent derivatives of cycloalkyl and heterocycloalkyl, respectively.

[0358] As used herein the terms “bicycloalkyl” and “bicycloheteroalkyl” refer to two cycloalkyl or cycloheteroalkyl groups that are bound to one another. Non-limiting examples include bicyclohexane and bipiperidine.

[0359] An “unsaturated hydrocarbon” has one or more double bonds or triple bonds. As used herein, the term “alkene” refers to an acyclic branched or unbranched hydrocarbons having one carbon-carbon double bond and the general formula CnH2n. Acyclic branched or unbranched hydrocarbons having more than one double bond are alkadienes, alkatrienes, and the like.

[0360] More particularly, the term “alkenyl” as used herein refers to a monovalent group derived from a C2-20inclusive straight or branched hydrocarbon moiety having at least one carbon-carbon double bond by the removal of a single hydrogen molecule. Alkenyl groups include, but are not limited to, ethenyl (i.e., vinyl), 2-propenyl, butenyl, l-methyl-2-buten-l-yl, pentenyl, 2- isopentenyl, hexenyl, octenyl, allenyl, butadienyl, crotyl (but-2-en-l-yl), 2-(butadienyl), 2,4- pentadienyl, 3-(l,4-pentadienyl), and the like, including higher homologs and isomers.

[0361] The term “cycloalkenyl” as used herein refers to a cyclic hydrocarbon containing at least one carbon-carbon double bond. Examples of cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadiene, cyclohexenyl, 1,3-cyclohexadiene, cycloheptenyl, cycloheptatrienyl, and cyclooctenyl.

[0362] The term “alkyne” as used herein refers to an acyclic branched or unbranched hydrocarbons having a carbon-carbon triple bond and the general formula CnH2n-2, RC=CR. Acyclic branched or unbranched hydrocarbons having more than one triple bond are known as alkadiynes, alkatriynes, and the like.

[0363] The term “alkynyl” as used herein refers to a monovalent group derived from a straight or branched C2-20hydrocarbon of a designed number of carbon atoms containing at least one carboncarbon triple bond. Examples of alkynyl groups include, but are not limited to, ethynyl, 2-propynyl (propargyl), 1-propynyl, pentynyl, hexynyl, and heptynyl groups, and the like.

[0364] As used herein, the term “alkylene” refers to an alkanediyl group having the free valencies on adjacent carbon atoms, e.g. -CH(CH3)CH2- propylene (systematically called propanc-1,2- diyl). More particularly, the term “alkylene” by itself or a part of another substituent refers to a straight or branched bivalent aliphatic hydrocarbon group derived from an alkyl group having from 1 to about 20 carbon atoms, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms. The alkylene group can be straight, branched or cyclic. The alkylene group also can be optionally unsaturated and / or substituted with one or more “alkyl group substituents.” There can be optionally inserted along the alkylene group one or more oxygen, sulfur or substituted or unsubstituted nitrogen atoms (also referred to herein as “alkylaminoalkyl”), wherein the nitrogen substituent is alkyl as previously described. Exemplary alkylene groups include methylene (-CH2- ); ethylene (-CH2-CH2-); propylene (-(CH2)3-); cyclohexylene (-C6H10-); -CH=CH-CH=CH-; -CH=CH-CH2-; -CH2CH2CH2CH2-, -CH2CH=CHCH2-, -CH2CsCCH2-, CH2CH2CH(CH2CH2CH3)CH2-, -(CH2)q-N(R)-(CH2)r-, wherein each of q and r is independently an integer from 0 to about 20, e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, and R is hydrogen or lower alkyl; methylenedioxyl (-O-CH2-O-); and ethylenedioxyl (-O-(CH2)2-O-). An alkylene group can have about 2 to about 3 carbon atoms and can further have 6-20 carbons. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being some embodiments of the present disclosure. A “lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms.

[0365] The term “hetero alkylene” by itself or as part of another substituent means a divalent group derived from heteroalkyl, as exemplified, but not limited by, -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-. For heteroalkylene groups, heteroatoms also can occupy either or both of the chain termini (e.g., alkyleneoxo, alkylenedioxo, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -C(O)OR’- represents both -C(O)OR’- and -R’OC(O)-.

[0366] The term “arene” refers to a monocyclic and polycyclic aromatic hydrocarbon.

[0367] The term “aryl” refers to a group derived from arenes by removal of a hydrogen atom from a ring carbon atom. Groups similarly derived from heteroarenes are sometimes subsumed in thisdefinition. An aryl group can include, for example, a single ring or multiple rings (such as from 2 to 3 rings), which are fused together or linked covalently.

[0368] The term “heteroaryl” refers to a group formed by removing one or more hydroxy groups from oxoacids that have the general structure RkE(=O)l(OH)m(10), and replacement analogues of such acyl groups. In organic chemistry an unspecified acyl group is commonly a carboxylic acyl group.

[0369] The term “heteroaryl” refers to the class of heterocyclyl groups derived from heteroarenes by removal of a hydrogen atom from any ring atom. A “heteroaryl” group can include from one to four heteroatoms (in each separate ring in the case of multiple rings) selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quatemized. A heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom. Non-limiting examples of aryl and heteroaryl groups include phenyl, 1 -naphthyl, 2-naphthyl, 4-biphenyl, 1 -pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2- imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3- isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5- thiazolyl, 2-furyl, 3-furyl, 2- thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4- pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1 -isoquinolyl, 5- isoquinolyl, 2-quinoxalinyl, 5- quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituents for each of above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below. The terms “arylene” and “heteroarylene” refer to the divalent forms of aryl and heteroaryl, respectively.

[0370] For brevity, the term “aryl” when used in combination with other terms (e.g., aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroaryl rings as defined above. Thus, the terms “arylalkyl” and “heteroarylalkyl” are meant to include those groups in which an aryl or heteroaryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl, furylmethyl, and the like) including those alkyl groups in which a carbon atom (e.g., a methylene group) has been replaced by, for example, an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(l- naphthyloxy)propyl, and the like). However, the term “haloaryl,” as used herein is meant to cover only aryls substituted with one or more halogens.

[0371] Where a heteroalkyl, heterocycloalkyl, or heteroaryl includes a specific number of members (e.g. “3 to 7 membered”), the term “member” refers to a carbon or heteroatom.

[0372] Each of above terms defined hereinabove (e.g. , “alkyl,” “heteroalkyl,” “cycloalkyl, and “hctcrocycloalkyl”, “alkenyl”, “alkynyl,” “aryl,” “hctcroaryl,” as well as their divalent derivatives) are meant to include both substituted and unsubstituted forms of the indicated group. Optional substituents for each type of group are provided below.

[0373] As used herein, the term “acyl” refers to a group formed by removing one or more hydroxy groups from oxoacids that have the general structure RkE(=O)l(OH)m(1 0), and replacementanalogues of such acyl groups. In organic chemistry an unspecified acyl group is commonly a carboxylic acyl group. For example, in some embodiments, the term acyl includes an organic acid group wherein the -OH of the carboxyl group has been replaced with another substituent and has the general formula RC(=O)-, wherein R is an alkyl, alkenyl, alkynyl, aryl, carbocylic, heterocyclic, or aromatic heterocyclic group as defined herein). As such, the term “acyl” specifically includes arylacyl groups, such as a 2-(furan-2-yl)acetyl)- and a 2-phenylacetyl group. Specific examples of acyl groups include acetyl and benzoyl. Acyl groups also are intended to include amides, -RC(=O)NR’, esters, -RC(=O)OR’, ketones, -RC(=O)R’, and aldehydes, -RC(=O)H.

[0374] The terms “alkoxyl” or “alkoxy” are used interchangeably herein and refer to a saturated (i.e., alkyl-O-) or unsaturated (i.e., alkenyl-O- and alkynyl-O-) group attached to the parent molecular moiety through an oxygen atom, wherein the terms “alkyl,” “alkenyl,” and “alkynyl” are as previously described and can include C1-20inclusive, linear, branched, or cyclic, saturated or unsaturated oxo-hydrocarbon chains, including, for example, methoxyl, ethoxyl, propoxyl, isopropoxyl, n-butoxyl, sec-butoxyl, tert-butoxyl, and n-pentoxyl, neopentoxyl, n-hcxoxyl, and the like.

[0375] The term “alkoxyalkyl” as used herein refers to an alkyl-O-alkyl ether, for example, a methoxyethyl or an ethoxymethyl group.

[0376] “Aryloxyl” refers to an aryl-O- group wherein the aryl group is as previously described, including a substituted aryl. The term “aryloxyl” as used herein can refer to phenyloxyl or hexyloxyl, and alkyl, substituted alkyl, halo, or alkoxyl substituted phenyloxyl or hexyloxyl.

[0377] “Aralkyl” refers to an aryl-alkyl-group wherein aryl and alkyl are as previously described, and included substituted aryl and substituted alkyl. Exemplary aralkyl groups include benzyl, phenylethyl, and naphthylmethyl.

[0378] “Aralkyloxyl” refers to an aralkyl-O- group wherein the aralkyl group is as previously described. An exemplary aralkyloxyl group is bcnzyloxyl, i.c., C6H5-CH2-O-. An aralkyloxyl group can optionally be substituted.

[0379] “Alkoxycarbonyl” refers to an alkyl-O-C(=O)- group. Exemplary alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, butyloxycarbonyl, and tert-butyloxycarbonyl.

[0380] “Aryloxycarbonyl” refers to an aryl-O-C(=O)- group. Exemplary aryloxycarbonyl groups include phenoxy- and naphthoxy-carbonyl.

[0381] “Aralkoxycarbonyl” refers to an aralkyl-O-C(=O)- group. An exemplary aralkoxycarbonyl group is benzyloxycarbonyl.

[0382] The term “acyloxyl” refers to an oxygen-centered radicals consisting of an acyl radical bonded to an oxygen atom, e.g., an acyl-O- group wherein acyl is as previously described.

[0383] The term “amine” refers to a compound formally derived from ammonia by replacing one, two or three hydrogen atoms by hydrocarbyl groups, and having the general structures RNH2(primary amines), R2NH (secondary amines), R3N (tertiary amines). In some embodiments, the term amino refers to the -NH2group. More generally, the amino group is -NR'R”, wherein R' and R” are typically selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0384] The terms “acylamino” and “alkylamino” refer to specific N-substituted organic radicals with acyl and alkyl substituent groups respectively.

[0385] An “aminoalkyl” as used herein refers to an amino group covalently bound to an alkylene linker. More particularly, the terms alkylamino, dialkylamino, and trialkylamino as used herein refer to one, two, or three, respectively, alkyl groups, as previously defined, attached to the parent molecular moiety through a nitrogen atom. The term alkylamino refers to a group having the structure -NHR’ wherein R’ is an alkyl group, as previously defined; whereas the term dialkylamino refers to a group having the structure -NR’R”, wherein R’ and R” are each independently selected from the group consisting of alkyl groups. The term trialkylamino refers to a group having the structure -NR’R”R”’, wherein R’, R”, and R’” are each independently selected from the group consisting of alkyl groups. Additionally, R’, R”, and / or R’” taken together may optionally be -(CH2)k- where k is an integer from 2 to 6. Examples include, but are not limited to,methylamino, dimethylamino, ethylamino, diethylamino, diethylaminocarbonyl, mcthylcthylamino, isopropylamino, pipcridino, trimcthylamino, and propylamino.

[0386] The terms alkylthioether and thioalkoxyl refer to a saturated (i.e., alkyl-S-) or unsaturated (i.e., alkenyl-S- and alkynyl-S-) group attached to the parent molecular moiety through a sulfur atom. Examples of thioalkoxyl moieties include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, and the like.

[0387] “Acylamino” refers to an acyl-NH- group wherein acyl is as previously described. “Aroylamino” refers to an aroyl-NH- group wherein aroyl is as previously described.

[0388] The term “carbonyl” refers to a compound containing the carbonyl group, -C(=O)-. The term is commonly used in the restricted sense of aldehydes (R-C(=O)H) and ketones, although it actually includes carboxylic acids and derivatives.

[0389] The term “carboxylic acid” refers to an oxoacids having the structure RC(=O)OH. The term is used as a suffix in systematic name formation to denote the -C(=O)OH group including its carbon atom. In some embodiments, the term “carboxyl” refers to the -COOH group. Such groups also are referred to herein as a “carboxylic acid” moiety.

[0390] “Carbamoyl” refers to an amide group of the formula -C(=O)NHi.

[0391] “Alkylcarbamoyl” refers to a R’RN-C(=O)- group wherein one of R and R’ is hydrogen and the other of R and R’ is alkyl and / or substituted alkyl as previously described.

[0392] “Dialkylcarbamoyl” refers to a R’RN-C(=O)- group wherein each of R and R’ is independently alkyl and / or substituted alkyl as previously described.

[0393] The term carbonyldioxyl, as used herein, refers to a carbonate group of the formula -O- C(=O)-OR.

[0394] The term “cyano” refers to the -C=N group.

[0395] The terms “halo,” “halide,” or “halogen” as used herein refer to fluoro, chloro, bromo, and iodo groups. Additionally, terms such as “haloalkyl,” are meant to include monohaloalkyl and polyhaloalkyl. For example, the term “halo(C1-4)alkyl” is mean to include, but not be limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

[0396] The term “hydroxyl” refers to the -OH group.

[0397] The term “hydroxy alkyl” refers to an alkyl group substituted with an -OH group.

[0398] The term “mercapto” refers to the -SH group.

[0399] The term “oxo compound” refers to a compounds containing an oxygen atom, =0, doubly bonded to carbon or another clement. The term thus embraces aldehydes, carboxylic acids, ketones, sulfonic acids, amides and esters. Oxo used as an adjective (and thus separated by a space) modifying another class of compound, as in oxo carboxylic acids, indicates the presence of an oxo substituent at any position. To indicate a double-bonded oxygen that is part of a ketonic structure, the term keto is sometimes used as a prefix, but such use has been abandoned by IUPAC for naming specific compounds. A traditional use of keto is for indicating oxidation of CHOH to C=O in a parent compound that contains OH groups, such as carbohydrates, e.g. 3-ketoglucose. In some embodiments, the term “oxo” as used herein means an oxygen atom that is double bonded to a carbon atom or to another element.

[0400] The term “nitro” refers to the -NO2 group.

[0401] The term “thio” refers to replacement of an oxygen by a sulfur, e.g., PhC(=S)NH2, thiobenzamide.

[0402] The term “thiol” refers to a compounds having the structure RSH (R H), e.g., MeCH2SH ethanethiol. A thiol also is known by the term “mercaptan.”

[0403] The term “thiohydroxyl” or “thiol,” as used herein, refers to a group of the formula -SH.

[0404] The term “sulfate” refers to the -SO4group.

[0405] The term “sulfide” refers to a compound having the structure RSR (RH) and also are referred to as “thioethers.”

[0406] The term “sulfone” refers to a compound having the structure, RS(=O)2R (RH), e.g., C2H5S(=O)2CH3ethyl methyl sulfone.

[0407] The term “sulfoxide” refers to a compound having the structure R2S=O (R H), e.g.,Ph2S=O diphenyl sulfoxide.

[0408] The term “ureido” refers to a urea group of the formula -NH — CO — NH2.

[0409] One of ordinary skill in the art would recognize that a structure represented generally by, for example, the formula:

[0410]

[0411] as used herein refers to a ring structure, for example, but not limited to a 3-carbon, a 4- carbon, a 5-carbon, a 6-carbon, a 7-carbon, and the like, aliphatic and / or aromatic cycliccompound, including a saturated ring structure, a partially saturated ring structure, and an unsaturated ring structure, comprising a substituent R group, wherein the R group can be present or absent, and when present, one or more R groups can each be substituted on one or more available carbon atoms of the ring structure. The presence or absence of the R group and number of R groups is determined by the value of the variable “n,” which is an integer generally having a value ranging from 0 to the number of carbon atoms on the ring available for substitution. Each R group, if more than one, is substituted on an available carbon of the ring structure rather than on another R group. For example, the structure above where n is 0 to 2 would comprise compound groups including, but not limited to:

[0412]

[0413] and the like.

[0414] A dashed line representing a bond in a cyclic ring structure indicates that the bond can be either present or absent in the ring. That is, a dashed line representing a bond in a cyclic ring structure indicates that the ring structure is selected from the group consisting of a saturated ring structure, a partially saturated ring structure, and an unsaturated ring structure.

[0415] The symbol denotes the point of attachment of a moiety to the remainder of themolecule.

[0416] When a named atom of an aromatic ring or a heterocyclic aromatic ring is defined as being “absent,” the named atom is replaced by a direct bond.

[0417] Throughout the specification and claims, a given chemical formula or name shall encompass all tautomers, congeners, and optical- and stereoisomers, as well as racemic mixtures where such isomers and mixtures exist.

[0418] Certain compounds of the present disclosure may possess asymmetric carbon atoms (optical or chiral centers) or double bonds; the enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisometric forms that may be defined, in terms of absolute stereochemistry, as (R)-or (S)- or, as D- or L- for amino acids, and individual isomers are encompassed within the scope of the present disclosure. The compounds of the present disclosuredo not include those which are known in art to be too unstable to synthesize and / or isolate. The present disclosure is meant to include compounds in racemic, scalcmic, and optically pure forms. Optically active (R)- and (S)-, or D- and L-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefenic bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.

[0419] Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the disclosure.

[0420] As used herein, the term “congener” refers to one of two or more substances related to each other by origin, structure, or function.

[0421] The term “enantiomer” refers to one of a pair of molecular entities which are mirror images of each other and non-superposable.

[0422] The term “stereoisomer” refers to an isomer that possess identical constitution, but which differ in the arrangement of their atoms in space.

[0423] The term “racemate” refers to an equimolar mixture of a pair of enantiomers. It does not exhibit optical activity. The chemical name or formula of a racemate is distinguished from those of the enantiomers by the prefix (±)- or rac- (or racem-) or by the symbols RS and SR.

[0424] The term “diastereoisomerism” refers to stereoisomerism other than enantiomerism. Diastereoisomers (or diastereomers) are stereoisomers not related as mirror images. Diastereoisomers are characterized by differences in physical properties, and by some differences in chemical behavior towards achiral as well as chiral reagents.

[0425] It will be apparent to one skilled in the art that certain compounds of this disclosure may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the disclosure. The term “tautomer,” as used herein, refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another.

[0426] Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures with the replacement of a hydrogen by a deuterium ortritium, or the replacement of a carbon by13C- or14C-enriched carbon are within the scope of this disclosure.

[0427] The compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (3H), iodine- 125 (125I) or carbon- 14 (14C). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.

[0428] The term “about,” when used in connection with one or more numbers or numerical ranges, should be understood to refer to all such numbers, including all numbers in a range and modifies that range by extending the boundaries slightly above and slightly below the numerical values set forth by, for example, in some embodiments, + / -20%, + / - 15%, + / -10%, +1-5%, + / -4%, +1-3%, + / - 2%, and + / -1%. The recitation of numerical ranges by endpoints includes all numbers, e.g., whole integers, including fractions thereof, subsumed within that range (for example, the recitation of 1 to 5 includes 1, 2, 3, 4, and 5, as well as fractions thereof, e.g., 1.5, 2.25, 3.75, 4.1, and the like) and any range within that range.

[0429] The phrase “in one embodiment” or “in some embodiments” as used herein does not necessarily refer to the same embodiment, though it may. Furthermore, the phrase “in another embodiment” as used herein does not necessarily refer to a different embodiment, although it may. Thus, as described below, various embodiments of the invention may be readily combined, without departing from the scope or spirit of the invention.

[0430] The terms “comprise(s),” “include(s),” “having,” “has,” “can,” “contain(s),” and variants thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that do not preclude the possibility of additional acts or structures. The singular forms “a,” “and” and “the” include plural references, i.e., “one or more,” unless the context clearly dictates otherwise. The present disclosure also contemplates other embodiments “comprising,” “consisting of’ and “consisting essentially of,” the embodiments or elements presented herein, whether explicitly set forth or not. Likewise, the term “include” and its grammatical variants are intended to be nonlimiting, such that recitation of items in a list is not to the exclusion of other like items that can be substituted or added to the listed items.EXAMPLES

[0431] The following Examples have been included to provide guidance to one of ordinary skill in the art for practicing representative embodiments of the presently disclosed subject matter. In light of the present disclosure and the general level of skill in the art, those of skill can appreciate that the following Examples are intended to be exemplary only and that numerous changes, modifications, and alterations can be employed without departing from the scope of the presently disclosed subject matter. The synthetic descriptions and specific examples that follow are only intended for the purposes of illustration and are not to be construed as limiting in any manner to make compounds of the disclosure by other methods.EXAMPLE 1[004321 Novel Pharmacological Mechanism to Block Stress-Induced Cortisol Production

[0433] This Example demonstrates that pharmacological inhibition of GCPIT s enzymatic activity, using the potent and selective inhibitor 2-PMPA, completely blocks the stress-induced increases in plasma aldosterone and corticosterone, while having no effect on the basal levels of these hormones.

[0434] GCPII inhibition increases plasma NAAG levels in mice confirming in vivo target engagement

[0435] Animals

[0436] C57BL / 6 mice were obtained from the National Institute on Aging (NIA) and housed under specific pathogen-free conditions at Johns Hopkins University. All procedures were approved by the relevant Institutional Animal Care and Use Committees. A combination of male and femaleC57BL / 6 mice were used. Mice were housed at a maximum of 5 per cage on a 12-hour dark / light cycle and provided food and water ad libitum. Mice were administered either 100 mg / kg 2-PMPA or vehicle (HEPES buffer) control via intraperitoneal (IP) injection 5 days per week for 10 months.

[0437] Plasma metabolites measurement

[0438] After 10 months of chronic 2-PMPA or vehicle treatment, 25-month-old mice were euthanized. Plasma samples were collected from the blood by centrifugation at 1500x g for 10 min in lithium heparin microtubes and stored at -80 °C until bioanalysis. Plasma metabolites were extracted from the samples using 80% methanol in mass-spectrometry grade water. The solvents were then removed using speed vacuum and lyophilization, after which the dried metabolites wereresuspended in 50% acetonitrile. Plasma metabolites were measured using liquid chromatographymass spectrometry (LC-MS) metabolomics analysis (Gigantest Inc).

[0439] Chronic 2-PMPA treatment significantly increased plasma NA AG levels

[0440] We confirmed GCPII enzyme inhibition by 2-PMPA treatment by demonstrating a 3.5- fold increase in plasma NAAG levels compared to vehicle control (FIG. 1). This significant elevation in circulating NAAG indicates robust inhibition of GCPII catalytic activity by chronic 2-PMPA administration.

[0441] GCPII inhibition dramatically decreases plasma aldosterone and corticosterone levels in old and frail mice (approximately 25-month-old mice)

[0442] Animals

[0443] C57BL / 6 mice were obtained from the National Institute on Aging (NIA) and housed under specific pathogen-free conditions at Johns Hopkins University. All procedures were approved by the relevant Institutional Animal Care and Use Committees. A combination of male and femaleC57BU6 mice were used. Mice were housed at a maximum of 5 per cage on a 12-hour dark / lighl cycle and provided food and water ad libitum. Mice were administered either 100 mg / kg 2-PMPA or vehicle (HEPES buffer) control via intraperitoneal (IP) injection 5 days per week for 10 months.

[0444] Plasma metabolites measurement

[0445] After 10 months of chronic 2-PMPA or vehicle treatment, 25-month-old mice were euthanized. Plasma samples were collected from the blood by centrifugation at 1500x g for 10 min in lithium heparin microtubes and stored at -80 °C until bioanalysis. Plasma metabolites were extracted from the samples using 80% methanol in mass-spectrometry grade water. The solvents were then removed using speed vacuum and lyophilization, after which the dried metabolites were resuspended in 50% acetonitrile. Plasma metabolites were measured using liquid chromatographymass spectrometry (LC-MS) metabolomics analysis (Gigantest Inc).

[0446] Chronic 2-PMPA treatment decreased plasma aldosterone and corticosterone levels

[0447] We found a significant decrease in plasma aldosterone and corticosterone levels in mice receiving chronic 2-PMPA treatment compared to vehicle-treated controls. This observation indicates that sustained GCPII inhibition by 2-PMPA reduces circulating levels of these stress- related steroids (FIG. 2).

[0448] GCPII inhibition completely normalizes the rise in stress-induced increases in plasma corticosterone and aldosterone following chronic social defeat stress in mice.

[0449] CSDS mouse model and 2-PMPA treatment

[0450] C57BL / 6 mice, obtained from the Jackson Laboratory, were kept in pathogcn-frcc facilities at Johns Hopkins University, with all procedures approved by relevant Institutional Animal Care and Use Committees. Chronic Social Defeat Stress (CSDS) was administered using our published method. Male CD-I mice, selected for aggression, were housed singly and used as resident aggressors against intruder C57 mice for daily 10-minute sessions over ten consecutive days. C57 mice exhibited characteristic CSDS behaviors, including escape, submission, and freezing, during these sessions, while controls were placed in similar cages without aggressor exposure. For GCPII treatment, C57 mice underwent 10 days of CSDS and received daily treatment with either GCPII inhibitor 2-PMPA (100 mg / kg, i.p.) or vehicle control (HEPES buffer).

[0451] ELISA for plasma steroid levels

[0452] 24 hours after 10 days of CSDS, C57 mice were euthanized, and blood was collected by cardiac puncture prior to refrigerated centrifugation (3,000 g for 10 min) to obtain plasma. Plasma steroid levels were measured using ELISA kits (corticosterone, Cat # ADI-900-097, Enzo; aldosterone, Cat # ADI-900-173, Enzo) in accordance with the manufacturer’s protocols.

[0453] 2-PMPA suppresses CSDS-induced upregulation of plasma steroid levels

[0454] We found that while CSDS elevated plasma corticosterone and aldosterone levels in C57 mice, chronic 2-PMPA administration significantly mitigated these increases in the CSDS group without affecting control mice, indicating 2-PMPA's peripheral anti-stress effect (FIG. 3).

[0455] GCP knockout (KO) in mice inhibited the CSDS-induced elevated plasma level of corticosterone (CORT) and aldosterone (ALDO).

[0456] CSDS Mouse Model Using GCP KO Mice

[0457] GCP KO mice and WT littermates were bred and maintained in pathogen-free facilities at Johns Hopkins University, with all procedures approved by relevant Institutional Animal Care and Use Committees. CSDS was administered using our published method. Male CD-1 mice, selected for aggression, were housed singly and used as resident aggressors against intruder test mice for daily 10-minute sessions over ten consecutive days. Test mice (CSDS WT littermates, referred to as CSDS W; CSDS GCP KO mice, referred to as CSDS G) exhibited characteristic CSDS behaviors, including escape, submission, and freezing, during these sessions, while controls (Control WT littermates, referred to as CTR W; Control GCP KO mice, referred to as CTR G) were placed in similar cages without aggressor exposure.

[0458] ELISA for plasma steroid, levels

[0459] 24 hours after 10 days of CSDS, GCP KO and WT littermate mice were euthanized, and blood was collected by cardiac puncture prior to refrigerated centrifugation (3,000 g for 10 min) to obtain plasma. Plasma steroid levels were measured using ELISA kits (CORT, Cat # ADI-900- 097, Enzo; ALDO, Cat # ADI-900-173, Enzo) in accordance with the manufacturer’s protocols.

[0460] GCP KO suppresses CSDS-induced upregulation of plasma steroid levels

[0461] We found that CSDS significantly increased plasma CORT and ALDO levels in WT mice (CSDS W) compared to control WT mice (CTR W). In contrast, GCP KO mice exposed to CSDS (CSDS G) showed plasma steroid levels similar to those of control KO mice (CTR G). These findings indicate that GCP KO mitigates the stress-induced elevation of plasma CORT and ALDO without altering baseline levels (FIG. 4).

[0462] GCP KO Improved CSDS-induced Recognition Memory Deficits and Alleviated CSDS-induced Social Avoidance.

[0463] Novel object recognition test (NORT)

[0464] The NORT was conducted in a Plexiglas arena with two identical objects placed at adjacent corners during the 10-minute training session. Mice were allowed to explore both objects freely. After a 30-minute interval, one familiar object was replaced with a novel object, and the test mice were given 5 minutes to explore. The percentage of time spent exploring the novel object relative to the total exploration time was calculated as the recognition index, reflecting recognition memory performance.

[0465] Social interaction test (SIT)

[0466] The SIT was performed in a three-chamber apparatus during a three-phase session. During the 10-minute habituation period, the test mouse was allowed to explore the entire apparatus. In the second phase, an inanimate object was placed in one side chamber, while the other chamber remained empty. In the final 10-minute phase, a novel mouse (stranger) was placed in one chamber while the other contained the inanimate object. The time spent in each chamber and the time spent sniffing were recorded. Normal social interaction was indicated by a preference for the chamber containing the stranger mouse, while reduced interaction suggested social avoidance.

[0467] GCP KO improved recognition memory deficits induced by CSDS

[0468] In the NORT, CSDS W mice showed significantly reduced exploration of the novel object compared to CTR W, indicating impaired recognition memory. In contrast, CSDS G mice spent asignificantly greater percentage of time sniffing the novel object compared to CSDS W. The performance of CSDS G mice was comparable to CTR W and CTR G, indicating that GCP KO prevented CSDS-induced recognition memory deficits (FIG. 5).

[0469] GCP KO alleviated, social avoidance induced by CSDS

[0470] In the SIT, CSDS W mice exhibited social avoidance, reflected by reduced time spent in the chamber with the stranger mouse and less sniffing interaction. CSDS G mice spent significantly more time in the chamber with the stranger mouse and engaged in prolonged sniffing compared to CSDS W mice. These behaviors in CSDS G mice were comparable to those of CTR W and CTR G, demonstrating that GCP KO alleviated CSDS-induced social avoidance (FIG. 6).REFERENCES

[0471] All publications, patent applications, patents, and other references mentioned in the specification are indicative of the level of those skilled in the art to which the presently disclosed subject matter pertains. All publications, patent applications, patents, and other references are herein incorporated by reference to the same extent as if each individual publication, patent application, patent, and other reference was specifically and individually indicated to be incorporated by reference. It will be understood that, although a number of patent applications, patents, and other references are referred to herein, such reference does not constitute an admission that any of these documents form part of the common general knowledge in the art.

[0472] Although the foregoing subject matter has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be understood by those skilled in the art that certain changes and modifications can be practiced within the scope of the appended claims.

Claims

THAT WHICH IS CLAIMED:

1. A method for reducing stress-induced hormone production in a subject in need thereof, the method comprising administering a therapeutically effective amount of a glutamate carboxypeptidase II (GCPII) inhibitor to the subject.

2. The method of claim 1, wherein the stress hormone is selected from aldosterone, corticosterone, and a combination thereof.

3. The method of claim 1, wherein the GCPII inhibitor is a compound of formula (I):wherein: R1and R2are each independently H or -OH; R3is OH; and R4is selected from the group consisting of -NH-X1, -COO-X1, -C(=O)-NH-CH2-C(=O)- O-X1, and -C(=O)-NH-CH2-CH2-S(=O)2-O-X1, wherein X1is selected from the group consisting of -(C=O)-(CH2)m-P(=O)(OH)-X2, -(C=O)-(CH2)m-CH(COOH)-CH2-P(=O)(OH)-X2, -CH2-O- (C=O)-(CH2)m-P(=O)(OH)-X2, -CH2-O-C(=O)-(CH2)m-CH(COOH)-CH2-P(=O)(OH)-X2, -CH2- O-C(=O)-(CH2)m-CH(COOH)-NH-(C=O)-NH-CH(COOH)-CH2-CH(CH3)2, -CH2-O-C(=O)-Ar- CH2-CH(COOH)-(CH2)m-C(=O)-NH-OH, -CH2-O-C(=O)-(CH2)m-X3, -CH2-O-C(=O)-Ar-CH2- X3, and a protecting group, wherein X2is selected from the group consisting of -OH, -CH2- CH(COOH)-(CH2)p-C(=O)-OH, and a protecting group, Ar is arylene, and X3is 2-oxotetrahydro- 2H-thiopyran-3-yl, and each m and p is independently selected from the group consisting of 1, 2, 3, and 4; or R3is selected from the group consisting of -O-C(=O)-O-CH2-O-C(=O)-(CH2)n- CH(COOH)-CH2-P(=O)(OH)2, and -O-C(=O)-CH2-CH2-P(=O)(OH)-CH2-CH(COOH)-(CH2)n-C(=O)-OH, wherein each n is independently an integer selected from the group consisting of 1 , 2, 3, and 4; and R4is selected from the group consisting of -NH2, -COOH, -C(=O)-NH-CH2-C(=O)-OH, and -C(=O)-NH-CH2-CH2-S(=O)2-OH; and phafflnaceutically acceptable salts the eof.

4. The method of claim 3, wherein:(i) R1and R2are both H;(ii) R1is H and R2is OH;(iii) R1is OH and R2is H; or(iv) R1and R2are both OH.

5. The method of claim 3, wherein:(i) R3is OH and R4is selected from the group consisting of -NH-X1, -COO-X1, -C(=O)- NH-CH2-C(=O)-O-X1, and -C(=O)-NH-CH2-CH2-S(=O)2-O-X1, wherein X1is selected from the group consisting of -(C=O)-CH2-CH2-P(=O)(OH)-X2, -(C=O)-CH2-CH2-CH(COOH)-CH2- P(=O)(OH)-X2, -CH2-O-(C=O)-CH2-CH2-P(=O)(OH)-X2, -CH2-O-C(=O)-CH2-CH2- CH(COOH)-CH2-P(=O)(OH)-X2, -CH2-O-C(=O)-CH2-CH2-CH(COOH)-NH-(C=O)-NH- CH(COOH)-CH2-CH(CH3)2, -CH2-O-C(=O)-Ar-CH2-CH(COOH)-CH2CH2-C(=O)-NH-OH, - CH2-O-C(=O)-CH2-CH2-X3, -CH2-O-C(=O)-Ar-CH2-X3, and a protecting group, wherein X2is selected from the group consisting of -OH, -CH2-CH(COOH)-CH2-CH2-CH(=O)-OH, and a protecting group, Ar is phenyl, and X3is 2-oxotetrahydro-2H-thiopyran-3-yl;(ii) R1is OH, R2is H, R3is OH, and R4is COO-X1, wherein X1is -CH2-O-C(=O)- (CH2)m-CH(COOH)-CH2-P(=O)(OH)-X2; o(iii) R1is H and R2is OH or R1is OH and R2is H, R3is OH, and R4is -NH-X1, wherein X1is -(C=O)-CH2-CH2-CH(COOH)-CH2-P(=O)(OH)-X2.

6. The method of claim 3, wherein the compound of formula (I) is selected from the group consisting of:

7. The method of claim 3, wherein R3is selected from the group consisting of -O- C(=O)-O-CH2-O-C(=O)-CH2-CH2-CH(COOH)-CH2-P(=O)(OH)2, and -O-C(=O)-CH2-CH2- P(=O)(OH)-CH2-CH(COOH)-CH2-CH2-C(=O)-OH, and R4is selected from the group consisting of -NH2, -COOH, -C(=O)-NH-CH2-C(=O)-OH, and -C(=O)-NH-CH2-CH2-S(=O)2-OH.

8. The method of claim 3, wherein the compound of formula (I) is selected from the group consisting of:

9. The method of claim 1, wherein the GCPII inhibitor is a hydroxamate-basedGCPII inhibitor of formula (Ila):wherein n is an integer selected from 0, 1, 2, and 3.

10. The method of claim 9, wherein the hydroxamate-based GCPII inhibitor comprises:

11. The method of claim 1 , wherein the GCPII inhibitor is a prodrug of a hydroxamate-based GCPII inhibitor of formula (llb):wherein: R1is selected from the group consisting of -C(=O)-O-R4and -Ar-C(=O)-O-R4;R2is selected from the group consisting of H, substituted and unsubstituted C1-C6alkyl, substituted and unsubstituted C3-C8cycloalkyl, substituted and unsubstituted C6-C12aryl, substituted and unsubstituted C6-C12heteroaryl, -(CR5R6)n-R7, -C(=O)-O-R7, -C(=O)-R7,-C(=O)- NR7R8, -(CR5R6)n-O-C(=O)-O-R7, -(CR5R6)n-Ar-O-C(=O)-R7; R3is selected from the group consisting of H, substituted and unsubstituted C1-C6alkyl, substituted and unsubstituted C3-C12cycloalkyl, substituted and unsubstituted C6-C12aryl, substituted and unsubstituted C5-C12hete oa yl;R4is selected from the group consisting of H, substituted and unsubstituted C1-C6alkyl, substituted and unsubstituted C3-C12cycloalkyl, substituted and unsubstituted C6-C12aryl, substituted and unsubstituted C5-C12heteroaryl, -(CR5R6)n-O-C(=O)-O-R9, and -(CR5R6)n-Ar-O- C(=O)-R9; each R5and R6is independently selected from the group consisting of H, C1-C10alkyl, and C6-C12a alkyl;R7is selected from the group consisting of H, and substituted and unsubstituted C1-C10alkyl, substituted and unsubstituted C1-C10heteroalkyl, substituted and unsubstituted C3-C16cycloalkyl, substituted and unsubstituted C3-C12cycloheteroalkyl, substituted and unsubstituted C3-C12cycloheteroalkenyl, substituted and unsubstituted C6-C12aryl, substituted and unsubstituted C6-C12heteroaryl, and substituted and unsubstituted C6-C12a alkyl; R8is selected from the group consisting of H, and substituted and unsubstituted C1-C6alkyl; R9is selected from the group consisting of H, and substituted and unsubstituted C1-C6alkyl; n is an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, and 6; is selected from the group consisting of substituted and unsubstituted C6-C12aryl, and substituted and unsubstituted C6-C12hete oa yl; and stereoisomers and pharmaceutically acceptable salts thereof.

12. The method of claim 11, wherein the compound of formula (llb) is selected from the group consisting of:wherein: R2is selected from the group consisting of substituted and unsubstituted C1-C6alkyl, substituted and unsubstituted C3-C8cycloalkyl, substituted and unsubstituted C6-C12aryl, substituted and unsubstituted C6-C12heteroaryl, -(CR5R6)n-R7, -C(=O)-O-R7, -C(=O)-R7,-C(=O)- NR7R8, -(CR5R6)n-O-C(=O)-O-R7, -(CR5R6)n-Ar-O-C(=O)-R7; R3is selected from the group consisting of H and substituted and unsubstituted C1-C6alkyl; R4is selected from the group consisting of H, substituted and unsubstituted C1-C6alkyl, - (CR5R6)n-Ar-O-C(=O)-R9, and -(CR5R6)n-O-C(=O)-O-R9; whe ein n is 1, R5and R6are H, Ar is phenyl, R9is selected from the group consisting of substituted C1-C3alkyl, and unsubstituted C1- C3alkyl; and stereoisomers and pharmaceutically acceptable salts thereof.

13. The method of claim 11, wherein R2is -(CR5R6)n-Ar-O-C(=O)-R7, n is 1, Ar is phenyl, and R7is substituted or unsubstituted C1-C6alkyl.

14. The method of claim 11, wherein the compound of formula (llb) is selected from the group consisting of:

15. The method of claim 11, wherein R2is -(CR5R6)n-R7, n is 1, and R7is substituted C3-C12cycloheteroalkenyl.

16. The method of claim 11, wherein the compound of formula (llb) is selected from the group consisting of:

17. The method of claim 11, wherein R2is -C(=O)-R7, and R7is unsubstituted C1-C6alkyl, substituted C1-C6alkyl, unsubstituted C6-C12aryl, or unsubstituted C6-C12aralkyl.

18. The method of claim 11, wherein the compound of formula (llb) is selected from the group consisting of:

19. The method of claim 11, wherein R2is -C(=O)-O-R7, and R7is unsubstituted C1-C6alkyl.

20. The method of claim 11, wherein the compound of formula (lib) is:

21. The method of claim 11, wherein R2is -C(=O)-NR7R8, R7is substituted C1-C6alkyl, or substituted C3-C16cycloalkyl, and R8is H.

22. The method of claim 11, wherein the compound of formula (llb) is selected from the group consisting of:

23. The method of claim 11, wherein the compound of formula (llb) is:

24. The method of claim 1, wherein the GCPII inhibitor is a compound of formula (Illa) or (Illb):wherein: each R1, R2, R3, and R4is independently selected from the group consisting of H, alkyl, Ar, -( CR5R6)n-Ar, (CR5R6)n-O-C(=O)-R7, -(CR5R6)n-C(=O)-O-R7, -(CR5R6)n-O-C(=O)-O-R7,- (CR5R6)n-O-R7, -(CR5R6)n-O-[(CR5R6)n-O]m-R7, -(CR5R6)n-Ar-O-C(=O)-R7,-Ar-C(=O)-O- (CR5R6)n-R7, -(CR5R6)n-NR8R9, and -(CR5R6)n-C(=O)-NR8R9, wherein n is an integer from 1 to 20, m is an integer from 1 to 20; each R3' and R4' are independently H oralkyl; each R5and R6is independently selected from the group consisting of H, alkyl, and alkyla^l; each R7is independently straight chain or branched alkyl; is aryl, substituted a yl, hete oa yl orsubstituted heteroayl; andR8and R9are each independently H o alkyl; and pharmaceutically acceptable salts thereof.

25. The method of claim 24, wherein the compound of formula (Illa) is selected from the group consisting of:

26. The method of claim 24, wherein compound of formula (Illb) is selected from:

27. The method of claim 24, wherein:(a) each R1is H; each R2is selected from the group consisting of H, alkyl, Ar, -(CR5R6)n-Ar, -(CR5R6)n-O- C(=O)-R7, -(CR5R6)n- C(=O)-O-R7, -(CR5R6)n-O-C(=O)-O-R7, -(CR5R6)n-O-R7, -(CR5R6)n-O- [(CR5R6)n-O]m-R7, -(CR5R6)n-Ar-O-C(=O)-R7, -Ar-C(=O)-O-(CR5R6)n-R7, -(CR5R6)n-NR8R9, and -(CR5R6)n-C(=O)-NR8R9; each R3is selected from the group consisting of H, alkyl, Ar, -(CR5R6)n-Ar, -(CR5R6)n-O- C(=O)-R7, -(CR5R6)n- C(=O)-O-R7, -(CR5R6)n-O-C(=O)-O-R7, -(CR5R6)n-O-R7, -(CR5R6)n-O- [(CR5R6)n-O]m-R7, -(CR5R6)n-Ar-O-C(=O)-R7, -Ar-C(=O)-O-(CR5R6)n-R7, -(CR5R6)n-NR8R9, and -(CR5R6)n-C(=O)-NR8R9; and each R4is selected from the group consisting of -(CR5R6)n-O-C(=O)-R7, -(CR5R6)n- C(=O)-O-R7, -(CR5R6)n-O-C(=O)-O-R7, -(CR5R6)n-O-R7, -(CR5R6)n-O-[(CR5R6)n-O]m-R7, -(CR5R6)n-Ar-O-C(=O)-R7, -Ar-C(=O)-O-(CR5R6)n-R7, -(CR5R6)n-NR8R9, and -(CR5R6)n-C(=O)- NR8R9;(b) each R1is alkyl; each R2is selected from the group consisting of H, alkyl, Ar, -(CR5R6)n-Ar, -(CR5R6)n-O- C(=O)-R7, -(CR5R6)n- C(=O)-O-R7, -(CR5R6)n-O-C(=O)-O-R7, -(CR5R6)n-O-R7, -(CR5R6)n-O- [(CR5R6)n-O]m-R7, -(CR5R6)n-Ar-O-C(=O)-R7, -Ar-C(=O)-O-(CR5R6)n-R7, -(CR5R6)n-NR8R9, and -(CR5R6)n-C(=O)-NR8R9; each R3is selected from the group consisting of H, alkyl, Ar, -(CR5R6)n-Ar, -(CR5R6)n-O- C(=O)-R7, -(CR5R6)n- C(=O)-O-R7, -(CR5R6)n-O-C(=O)-O-R7, -(CR5R6)n-O-R7, -(CR5R6)n-O- [(CR5R6)n-O]m-R7, -(CR5R6)n-Ar-O-C(=O)-R7, -Ar-C(=O)-O-(CR5R6)n-R7, -(CR5R6)n-NR8R9, and -(CR5R6)n-C(=O)-NR8R9; and each R4is selected from the group consisting of Ar, -(CR5R6)n-O-C(=O)-R7, -(CR5R6)n- C(=O)-O-R7, -(CR5R6)n-O-C(=O)-O-R7, -(CR5R6)n-O-R7, -(CR5R6)n-O-[(CR5R6)n-O]m-R7, - (CR5R6)n-Ar-O-C(=O)-R7, -Ar-C(=O)-O-(CR5R6)n-R7, -(CR5R6)n-NR8R9, and -(CR5R6)n-C(=O)- NR8R9;(c) each R1is-(CR5R6)n-Ar; each R2is selected from the group consisting of H, alkyl, Ar, -(CR5R6)n-Ar, -(CR5R6)n-O- C(=O)-R7, -(CR5R6)n- C(=O)-O-R7, -(CR5R6)n-O-C(=O)-O-R7, -(CR5R6)n-O-R7, -(CR5R6)n-O- [(CR5R6)n-O]m-R7, -(CR5R6)n-Ar-O-C(=O)-R7, -Ar-C(=O)-O-(CR5R6)n-R7, -(CR5R6)n-NR8R9, and -(CR5R6)n-C(=O)-NR8R9; each R3is selected from the group consisting of H, alkyl, Ar, -(CR5R6)n-Ar, -(CR5R6)n-O- C(=O)-R7, -(CR5R6)n- C(=O)-O-R7, -(CR5R6)n-O-C(=O)-O-R7, -(CR5R6)n-O-R7, -(CR5R6)n-O- [(CR5R6)n-O]m-R7, -(CR5R6)n-Ar-O-C(=O)-R7, -Ar-C(=O)-O-(CR5R6)n-R7, -(CR5R6)n-NR8R9, and -(CR5R6)n-C(=O)-NR8R9; and each R4is selected from the group consisting of Ar, -(CR5R6)n-O-C(=O)-R7, -(CR5R6)n- C(=O)-O-R7, -(CR5R6)n-O-C(=O)-O-R7, -(CR5R6)n-O-R7, -(CR5R6)n-O-[(CR5R6)n-O]m-R7, - (CR5R6)n-Ar-O-C(=O)-R7, -Ar-C(=O)-O-(CR5R6)n-R7, -(CR5R6)n-NR8R9, and -(CR5R6)n-C(=O)- NR8R9; or(d) each R1is selected from Ar, -(CR5R6)n-O-C(=O)-R7, -(CR5R6)n- C(=O)-O-R7, - (CR5R6)n-O-C(=O)-O-R7, -(CR5R6)n-O-R7, -(CR5R6)n-O-[(CR5R6)n-O]m-R7, -(CR5R6)n-Ar-O- C(=O)-R7, -Ar-C(=O)-O-(CR5R6)n-R7, -(CR5R6)n-NR8R9, and -(CR5R6)n-C(=O)-NR8R9;each R2is selected from the group consisting of H, alkyl, Ar, -(CR5R6)n-Ar, -(CR5R6)n-O- C(=O)-R7, -(CR5R6)n- C(=O)-O-R7, -(CR5R6)n-O-C(=O)-O-R7, -(CR5R6)n-O-R7, -(CR5R6)n-O- [(CR5R6)n-O]m-R7, -(CR5R6)n-Ar-O-C(=O)-R7, -Ar-C(=O)-O-(CR5R6)n-R7, -(CR5R6)n-NR8R9, and -(CR5R6)n-C(=O)-NR8R9; each R3is selected from the group consisting of H, alkyl, Ar, -(CR5R6)n-Ar, -(CR5R6)n-O- C(=O)-R7, -(CR5R6)n- C(=O)-O-R7, -(CR5R6)n-O-C(=O)-O-R7, -(CR5R6)n-O-R7, -(CR5R6)n-O- [(CR5R6)n-O]m-R7, -(CR5R6)n-Ar-O-C(=O)-R7, -Ar-C(=O)-O-(CR5R6)n-R7, -(CR5R6)n-NR8R9, and -(CR5R6)n-C(=O)-NR8R9; and each R4is selected from the group consisting of H, alkyl, Ar, -(CR5R6)n-Ar, -(CR5R6)n-O- C(=O)-R7, (CR5R6)n- C(=O)-O-R7, (CR5R6)n-O-C(=O)-O-R7, -(CR5R6)n-O-R7, -(CR5R6)n-O- [(CR5R6)n-O]m-R7, -(CR5R6)n-Ar-O-C(=O)-R7, -Ar-C(=O)-O-(CR5R6)n-R7, -(CR5R6)n-NR8R9, and -(CR5R6)n-C(=O)-NR8R9; wherein: each n is an integer from 1 to 20; each m is an integer from 1 to 20; each R5and R6is independently selected from the group consisting of H, alkyl, and alkylaryl; each R7is independently straight chain or branched alkyl; each Ar is aryl, substituted aryl, heteroaryl or substituted heteroaryl; each R8and R9are independently H or alkyl; and each R3' and R4' are independently H or alkyl; and pharmaceutically acceptable salts thereof.

28. The method of claim 24, wherein the compound is a compound of formula (Illa) and: R1is H; R2and R3are each selected from the group consisting of H, -(CR5R6)n-O-R7. -(CR5R6)n- Ar-O-C(=O)-R7, -(CR5R6)n-O-C(=O)-R7, -Ar-C(=O)-O-(CR5R6)n-R7, and -(CR5R6)n-O-C(=O)-O- R7; and R4is selected from the group consisting of -(CR5R6)n-O-R7, -(CR5R6)n-Ar-O-C(=O)-R7, - Ar-C(=O)-O-(CR5R6)n-R7, -(CR5R6)n-O-C(=O)-R7and -(CR5R6)n-O-C(=O)-O-R7; andpharmaceutically acceptable salts thereof.

29. The method of claim 24, wherein the compound is a compound of formula (Illa) and: R1is alkyl; R2and R3are each independently selected from the group consisting of H, alkyl, - (CR5R6)n-O-R7, -(CR5R6)n-Ar-O-C(=O)-R7, -(CR5R6)n-O-[(CR5R6)n-O]m-R7, -(CR5R6)n-O- C(=O)-R7and -(CR5R6)n-O-C(=O)-O-R7; and R4is selected from the group consisting of -(CR5R6)n-O-R7-(CR5R6)n-Ar-O-C(=O)-R7, - (CR5R6)n-O-[(CR5R6)n-O]m-R7, -(CR5R6)n-O-C(=O)-R7and -(CR5R6)n-O-C(=O)-O-R7; and pharmaceutically acceptable salts thereof.

30. The method of claim 24, wherein the compound is a compound of formula (Illa) and: R1is selected from -(CR5R6)n-O-C(=O)-R7and -(CR5R6)n-O-C(=O)-O-R7; and R2R3, and R4are each independently selected from H, Ar, -(CR5R6)n-O-C(=O)-R7, and - (CR5R6)n-O-C(=O)-O-R7; and pharmaceutically acceptable salts thereof.

31. The method of claim 24, wherein the compound is a compound of formula (Illa) and: one of R1, R2, R3, or R4is H and the other three are each independently selected from the group consisting of:-(CR5R6)n-O-C(=O)-R7and -(CR5R6)n-O-C(=O)-O-R7; wherein R5and R6are each independently selected from the group consisting of H, C1-8straight-chain alkyl, and C1-8branched-chain alkyl; R7is C1-8straight-chain alkyl, and C1-8branched-chain alkyl; and pharmaceutically acceptable salts thereof.

32. The method of claim 24, wherein the compound is a compound of formula (Illa) and:R2is H; and R1, R3, and R4are each independently selected from the group consisting of: -(CR5R6)n-O-C(=O)-R7and -(CR5R6)n-O-C(=O)-O-R7; wherein R5and R6are each independently selected from the group consisting of H, C1-8straight-chain alkyl, and C1-8branched-chain alkyl; R7is C1-8straight-chain alkyl or C1-8branched-chain alkyl; and pharmaceutically acceptable salts thereof.

33. The method of claim 24, wherein R5and R6are each H.

34. The method of claim 1, wherein the GCPII inhibitor is a compound of formula (IV):wherein:indicates that the bond can be a single or a double bond; R1is:-OR5, wherein R5is selected from the group consisting of H, C1-C8alkyl, and -O-(CH2)n- R6, wherein n is an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, and 8 and R6is substituted or unsubstituted aryl or heteroaryl; or -NR7R8, wherein R7and R8are each independently selected from the group consisting of H, C1-C4alkyl, C3-C6cycloalkyl, C1-C8alkoxyl, unsubstituted or substituted aryl or heteroaryl, -(CH2)m-R9, wherein R9is -OR10or CHX2, wherein R10is H or C1-C4alkyl, and each X is halogen, and -(CH2)m-CH(NH2)(COOH), wherein each m is independently an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, and 8; R2is H or -NR11R12, wherein R11and R12are each independently selected from the group consisting of H, C1-C4alkyl, and -C(=O)-R13, wherein R13is C1-C4alkyl or-C(NH2)-(CH2)p-R14, wherein R14is C1-C4alkyl or -NR15R16, wherein R15and R16are each H or C1-C4alkyl, and p is an integer selected from the group consisting of O, 1, 2, 3, 4, 5, 6, 7, and 8; R3and R4are each independently H or -C(=O)-R17, wherein R17is C1-C8alkyl or -(CH2)t-O-C(=O)-O-R18, wherein R18is C1-C8alkyl, and t is an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, and 8; and stereoisomers and pharmaceutically acceptable salts thereof.

35. The method of claim 34, wherein:(i) R1is -OR5, and R5is selected from the group consisting of H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec -butyl, tert-butyl, n-pentyl, sec-pentyl, isopentyl, neopentyl, n- hexyl, sec-hexyl, n-heptyl, and n-octyl;(ii) R1is -OR5, and R5is H or -O-(CH2)n-R6, wherein R6is substituted or unsubstituted phenyl;(iii) R1is -NR7R8, and R7is H or C1-C4alkyl and R8is selected from the group consisting of H, C1-C4alkyl, C3-C6cycloalkyl, unsubstituted or substituted phenyl, -(CH2)m-R9, wherein R9is -OR10or CHX2, wherein R10is H or C1-C4alkyl, and each X is halogen, and -(CH2)m- CH(NH2)(COOH), wherein each m is independently an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, and 8; or(iv) R2is -NR11R12, wherein R11is H and R12is H or -C(=O)-R13, wherein R13is C1-C4alkyl or -C(NH2)-(CH2)p-R14, wherein R14is C1-C4alkyl or -NR15R16, wherein R15and R16are each H or C1-C4alkyl, and p is an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, and 8.

36. The method of claim 34, wherein:(i) R3and R4are each H;(ii) if R1is -OR5, then R5cannot be H; or(iii) if R1is -OR5, then R3, R4, and R5cannot all be H.

37. The method of claim 34, wherein R3and R4are each independently selected from the group consisting of -C(=O)-CH3, -C(=O)-C(CH3)3, and -CH2-O-C(=O)-O-CH(CH3)2.

38. The method of claim 34, wherein the compound of formula (IV) is selected from the group consisting of:

39. The method of claim 1, wherein the GCP-II inhibitor is selected from: 2-[[methylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[ethylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[propylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[butylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[cyclohexylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[phenylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(phenylmethyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[((2-phenylethyl)methyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[((3-phenylpropyl)methyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[((3-phenylbutyl)methyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[((2-phenylbutyl)methyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[(4-phenylbutyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[(aminomethyl)hydroxyphosphinyl]methyl]pentanedioic acid;7-(L-2-amino-2-carboxyethylthio)-2-(2,2-dimethylcyclopropanecarboxamide)-2-heptenoic acid;2-(phosphonomethyl)pentanedioic acid;N-[methylhydroxyphosphinyl]glutamic acid;N-[ethylhydroxyphosphinyl]glutamic acid;N-[propylhydroxyphosphinyl]glutamic acid;N-[butylhydroxyphosphinyl]glutamic acid;N-[phenylhydroxyphosphinyl]glutamic acid; andN-[(phenylmethyl)hydroxyphosphinyl]glutamic acid.

40. The method of claim 1, wherein the GCPII inhibi tor is a compound of formula(V):wherein R is H or C1-C4alkyl, and R’ is benzyl; or a compound of formula (V”):wherein R is selected from H, 4-fluorobenzoyl, and 6-(fluorescein-5-carboxamido)hexanoyl.

41. The method of claim 1, wherein the GCPII inhibitor is selected from 3-(2- mercaptoethyl)biphenyl-2,3-dicarboxylic acid (E2072) and GPI-5693:

42. The method of claim 1, wherein the GCPII inhibitor is selected from MIP-1555, MIP-1519, MIP-1545, MIP-1427, MIP-1428, MIP-1379, MIP-1072, MIP-1095, MIP-1558, MIP-1405, MIP-1404, PSMA I&T, PSMA-617, PSMA-11, DCIBzL,18F-DCFPyl, ZJ 38, GCPII- IN-l, and JB-352.

43. The method of claim 1, wherein the GCPII inhibitor is a dendrimer conjugate of 2-PMPA, 2-MPPA, or other GCPII inhibitor.

44. The method of claim 1, wherein the GCPII inhibitor is 2-(phosphonomcthyl)- pentanedioic acid (2-PMPA).

45. The method of claim 1, wherein administering the therapeutically effective amount of the GCPII inhibitor comprises blocking a stress-induced increase in plasma levels of the stress-induced hormone.

46. The method of claim 45, wherein the blocking of the stress-induced increase in plasma levels of the stress-induced hormone has no effect on a basal level of the stress-induced hormone.

47. A method for treating a disease, disorder, or condition in a subject in need of treatment thereof, the method comprising reducing stress-induced hormone production in the subject by administering a therapeutically effective amount of a glutamate carboxypeptidase II (GCPII) inhibitor to the subject.

48. The method of claim 47, wherein the disease, disorder, or condition comprises a stress-related psychiatric disorder.

49. The method of claim 48, wherein the stress-related psychiatric disorder is selected from depression, anxiety, bipolar disorder, and obsessive-compulsive disorder.

50. The method of claim 47, wherein the disease, disorder, or condition comprises a neurodegenerative disease.

51. The method of claim 50, wherein the neurodegenerative disease is selected from Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, multiple sclerosis, muscular dystrophy, and Huntington's disease.

52. The method of claim 51, comprising slowing onset or progression of Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, multiple sclerosis, muscular dystrophy, and Huntington's disease.

53. The method of claim 47, wherein the disease, disorder, or condition comprises a cardiovascular disease.

54. The method of claim 53, comprising reducing a risk of a heart attack or a stroke.

55. The method of claim 53, comprising lowering one or more clinical conditions regulated by plasma stress hormones.

56. The method of claim 55, wherein the one more clinical conditions is selected from blood cholesterol levels, triglyceride levels, blood sugar levels, blood pressure, and arterial stiffness.

57. The method of claim 47, wherein the disease, disorder, or condition comprises Cushing syndrome.

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