Enantiomeric steroid modulators and uses thereof

Abstract

Among the various aspects of the present disclosure is the provision of enantiomeric steroid modulator compositions and methods of use thereof. Disclosed herein is an enantiomeric steroid modulator composition comprising ent-[17α-hydroxyprogesterone caproate]. A method to treat or prevent age-related macular degeneration (AMD) that includes administering an enantiomeric steroid modulator composition to a subject in need is also disclosed. A method to treat or prevent a pregnancy complication that includes administering an enantiomeric steroid modulator composition to a subject in need is also disclosed.

Description

[0001] ENANTIOMERIC STEROID MODULATORS AND USES THEREOF

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Patent Application Nos. 63 / 650,605 and 63 / 650,615, filed May 22, 2024, the entire disclosures of which are incorporated herein by reference.

[0004] GOVERNMENT SUPPORT CLAUSE

[0005] This invention was made with government support under MH122379 awarded by the National Institutes of Health. The government has certain rights in the invention.

[0006] FIELD OF THE INVENTION

[0007] The present disclosure generally relates to enantiomeric steroid modulator compositions and related methods of use thereof.

[0008] BACKGROUND OF THE INVENTION

[0009] Age-related macular degeneration (AMD) is a leading cause of blindness in people over 65 years old, with the dry form of AMD accounting for almost 90% of all cases. Sadly, no cure for dry AMD exists, and effective treatments are still being developed. The earliest sign of AMD is an accumulation of cellular debris called drusen, that is a result of dysfunction of the caretaker tissue responsible for the maintenance of the retina- retinal pigment epithelium (RPE). Hence, understanding the factors that cause RPE dysfunction is paramount for prevention and treatment of ocular diseases, such as AMD. To maintain transport of nutrients, support healthy retina and maintain immune privilege of the eye, the RPE relies on a specific set of ion channels, with the inwardly rectifying potassium channel Kir7.1 playing a critical role. Ion channels are transmembrane proteins, and some of these ion channels are regulated by neurosteroids, which levels decline with age. Recent research indicates that the fluctuations in such steroids may directly affect AMD progression. However, the molecular mechanisms behind this phenomenon were not completely understood, until recent work shed light on the problem. The Lishko group has been studying the effect of steroids on the regulation of epithelial ion channels, specifically focusing on Kir7.1. This team has made a groundbreaking discovery revealing that progesterone (P4) potently and directly activates Kir7.1 , an essential RPE protein. Kir7.1 is known to be vital for normal RPE physiology, as loss-of-function mutations in humans causes profound pathophysiology of RPE and blindness, and RPE-specific deletion of this channel in mice leads to photoreceptor degradation. They have also confirmed that recombinant human and murine Kir7.1 and Kir7.1 expressed in murine RPE are activated by selective neurosteroids directly and in the identical manner. These preliminary results provide strong evidence of the molecular mechanism of P4- driven control of RPE physiology and support the evidence that Kir7.1 has emerged as a promising novel therapeutic target to sustain normal RPE function. The ion channels are traditionally well-recognized druggable targets and Kir7.1 represents a well-validated one. The scientific premise of this disclosure is based on the observation that the age-associated changes and decline in the level of neurosteroids lead to suboptimal operation of Kir7.1 in RPE, which translates into RPE dysfunction. This pathology leads to altered transepithelial ion transport, cellular debris accumulation in the subretinal space, drusen formation, inflammation, all of which eventually triggers retinopathy and AMD. Thus, to sustain healthy RPE, the function of its essential potassium channel, Kir7.1 , must be maintained at a high level. Therefore, pharmacological activation of Kir7.1 could compensate for the age-related loss-of-function triggered by the changes in the levels of circulating neurosteroids. The present disclosure identified potent Kir7.1 modulators some of which are 2-fold and 22-fold more potent than P4. These compounds and the proposed search for other selective Kir7.1 activators will provide starting points to develop a much-needed therapy for dry AMD.

[0010] Preterm birth is detrimental to the well-being of both the mother and the newborn. During normal gestation, the myometrium is maintained in a quiescent state by the action of progesterone. As a steroid hormone, progesterone is thought to modify uterine and placental morphology by altering gene expression, as well as exhibiting its direct effect via nongenomic mode of action29. Recent reporting11 18revealed the nongenomic molecular mechanism of progesterone via activation of human inwardly rectifying potassium channel Kir7.1 , which is expressed in mammalian myometrial smooth muscle38and placental pericytes during late gestation11 18. Kir7.1 is also activated by compounds used to prevent premature labor, including the progestagens 17-alpha-hydroxyprogesterone caproate and dydrogesterone11 18revealing an unexpected mode of action for these drugs. These results reveal that Kir7.1 is the molecular target of endogenous and synthetic steroids that control uterine excitability and placental function and is therefore a promising therapeutic target to control utero-placental physiology and support healthy pregnancy.

[0011] The uterus during parturition produces strong and synchronized myometrial contractions ensuring successful delivery. However, during pregnancy it must remain quiescent to support the developing fetus and prevent premature labor. The uterine contractility is controlled by endocrine factors, including steroid hormone progesterone (P4) making it a steroid-responsive organ. In humans, the majority of P4 during pregnancy is produced by the placenta28, a heavily vascularized organ that also supports embryogenesis and provides nutrient exchange between the mother and the fetus. For more than 50 years, high circulating levels of P4 have been recognized as the main factor supporting pregnancy and uterine quiescence, but its molecular mechanism of action on the myometrium was not clearly understood29'3334'35. It has been shown that the rapid and reversible uterine relaxation can be observed upon acute application by P4 to isolated myometrial strips29 34.

[0012] Recently, it has been reported that uterine contractility is controlled by progesterone via inwardly rectifying potassium channel, Kir7.1 - the protein expressed in the specific uterine compartment adjacent to the placenta11 18Kir7.1 functional uterine expression is restricted to late gestation and is essential to keep the myometrium quiescent38. Both murine and human Kir7.1 are activated by progesterone via a non-genomic mechanism. Moreover, a comprehensive steroid- sensitivity profile revealed that Kir7.1 can only be activated by two endogenous and pregnancy-related hormones: dehydroepiandrosterone (DHEA) and P4, while other endogenous steroids fail to activate Kir7.110’11. Additionally, two therapeutic compounds used to prevent preterm labor and potentially treat preeclampsia: 17- alpha-hydroxyprogesterone caproate and dydrogesterone, that were believed to act via the nuclear progesterone receptor have been reported11. These compounds were revealed to be potent activators of Kir7.1 . These data reveal the previously unknown mechanism of action of steroid therapeutic compounds used to maintain pregnancy outcome and provide strong evidence for a nongenomic mechanism behind the rapid control of uterine excitability by progesterone. Additionally, functional expression of Kir7.1 in placental pericyte-specific mural cells that control the blood supply to the fetus has been reported. Given that placental pericyte dysfunction is linked to preeclampsia3637, and the fact that the aforementioned therapeutical compounds are currently being investigated as potential therapeutical intervention for preeclampsia, the instant disclosure supports the notion that Kir7.1 is a promising molecular target to control uteroplacental physiology.

[0013] As mentioned above, a potent regulator of Kir7.1 was identified as a synthetic progestin and FDA-approved drug for preterm labor prevention known as 17-hydroxyprogesterone-caproate (17OHP4) or Makena™, which potentially can enhance the function of Kir7.1 -expressing cells and restore their normal functions. However, 17OHP4 is not specific to Kir7.1 and can also interact with genomic progesterone (P4) receptor, which makes it a less desirable therapeutical compound.

[0014] Accordingly, the present disclosure is also directed to enantiomeric steroids targeting the specific potassium channel required to keep myometrial cells quiescent during late gestation (protein name Kir7.1 ) which supports the function of placental pericytes and is potently and specifically regulated by enantiomeric steroids of progesterone (ent-progesterone or ent-P4) and 17- hydroxyprogesterone-caproate (ent-17OHP4 or enf-Makena), which is twice and 10-fold more potent than progesterone (P4) and 17-hydroxyprogesterone-caproate (17OHP4), respectively. These two compounds provide potential pharmacological intervention and thus, provide starting points to develop a much-needed therapy for treatment of pregnancy complications, such as preterm labor and preeclampsia. Importantly, ent-17OHP4 is a new compound that has never been synthesized before.

[0015] SUMMARY OF THE INVENTION

[0016] Among the various aspects of the present disclosure is the provision of enantiomeric steroid modulator compositions and methods of use thereof. Briefly, therefore, the present disclosure is directed to enantiomeric steroid compositions that perform modulation of Kir7.1 and their use in the treatment of retinal diseases.

[0017] In addition, the present disclosure is also directed to enantiomeric steroid compositions that perform modulation of Kir7.1 and their use in the treatment of pregnancy complications.

[0018] The present teachings include compositions comprising a compound of Formula I wherein: Ri is independently selected from the group consisting of hydrogen, methyl, and ethyl; R2 is independently selected from the group consisting of straight-chained or branched alkyl, straight-chained or branched alkenyl, and straight-chained or branched alkynyl, or a pharmaceutically acceptable salt thereof.

[0019] The present teachings also include methods of preventing or treating age- related macular degeneration (AMD) comprising administering a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.

[0020] The present teachings also include methods of preventing or treating age- related macular degeneration (AMD) comprising administering a therapeutically effective amount of a composition comprising enf-progesterone, or a pharmaceutically acceptable salt thereof.

[0021] The present teachings also include methods of preventing or treating a pregnancy complication comprising administering a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.

[0022] The present teachings also include methods of preventing or treating a pregnancy complication comprising administering a therapeutically effective amount of a composition comprising ent-progesterone, or a pharmaceutically acceptable salt thereof.

[0023] The present teachings also include a method of preparing enf-[17o- hydroxy prog esterone caproate] (6) comprising the steps of:

[0024] 1 ) converting ent-testosterone to ent-androstenedione (1 );

[0025] 2) converting ent-androstenedione (1 ) to ent-[(17a)-17-hydroxy-3- oxoandrost-4-ene-17-carbo nitrile] (2);

[0026] 3) converting enf-[(17a)-17-hydroxy-3-oxoandrost-4-ene-17-carbonitrile] (2) to ent-[17a-3,3-(1 ,2-ethanediylbis(oxy))-17-hydroxyandrost-5-ene-17- carbonitrile] (3);

[0027] 4) converting enf-[17a-3,3-(1 ,2-ethanediylbis(oxy))-17-hydroxyandrost- 5-ene-17-carbonitrile] (3) to enf-[(17a)-3,3-(1 ,2-ethanediylbis(oxy))-17-(1- ethoxyethoxy)-androst-5-ene-17-carbonitrile] (4);

[0028] 5) converting ent-[(17a)-3,3-(1 ,2-ethanediylbis(oxy))-17-(1- ethoxyethoxy)-androst-5-ene-17-carbonitrile] (4) to enf-[17o-hydroxyprogesterone] (5);

[0029] 6) converting enf-[17a-hydroxyprogesterone] (5) to ent-[17a- hydroxy prog esterone caproate] (6).

[0030] Other objects and features will be in part apparent and in part pointed out hereinafter.

[0031] DESCRIPTION OF THE DRAWINGS

[0032] The patent or application file contains at least one drawing executed in color. Copies of this patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.

[0033] Those of skill in the art will understand that the drawings, described below, are for illustrative purposes only. The drawings are not intended to limit the scope of the present teachings in any way.

[0034] Figure 1A shows an inwardly rectifying current, characteristic for Kir7.1

[0035] (blue), is detected in whole cell recordings from murine RPE cells and is activated by P4 (red) and inhibited by murine Kir7.1 specific antagonist VU590 (black).

[0036] Figure 1 B shows immunostaining from an isolated RPE cell showing membrane Kir7.1 localization (red). Nuclei are stained by DAPI (blue).

[0037] Figure 10 shows fold increase in RPE Kir7.1 current that is potentiated by P4. In the presence of the Kir7.1 inhibitor, VLI590, the potentiation of the current by 10 pM P4 was prevented.

[0038] Figure 1 D shows left: recombinant murine Kir7.1 (mKir7.1 ) expressed in HEK293 is potently activated by P4 (red). Upper panel: control HEK293 cells transfected with empty vector lacking Kir7.1 fail to respond to P4. Lower panel: Kir7.1 expressing HEK293 cells recapitulate P4 activation of native Kir7.1 . Activated current is blocked by VU590 (black). Right: same as left. But with recombinant human Kir7.1 (hKir7.1 ).

[0039] Figure 1 E shows HEK293 transfected with plRES2-eGFP-hKir7.1 or mKir7.1 .

[0040] Figure 1 F shows the average current fold increase of hKirZ.1 recorded from HEK293 that were exposed to 10 pM of P4, estrogen (E2), estrone (E4), DHEA-S, cortisol (Cort), and DHEA. Transfection with hKir7.1 showed up to six-fold potentiation of the current after the addition of 10 pM P4. Dose-response of mKir7.1 and hKirZ.1 potentiation by p4 recorded from HEK293 as in (Fig. 1 D) and calculated using the averaged current density for n cells. Data are means ± SEM.

[0041] Figure 1 G shows a graph depicting the fold change in IK^. I after exposure to P4, comparing control HEK293 cells (black), HEK293 cells transfected with plRES-eGFP-Kir7.1 (red), and murine RPE cells (brown). P4 activated Kir7.1 in HEK293 cells regardless of the presence of 1 mM GDP-p-S (purple), a G- protein signaling blocker. This indicates that P4 activation of Kir7.1 does not involve G-protein signaling, suggesting direct binding to Kir7.1 . Data are presented as means ± S.E.M.; n.s. indicates nonsignificant differences.

[0042] Figure 1 H shows the average current fold increase of h Kir7.1 recorded from HEK293 that were exposed to 10 pM of corresponding steroids: P4; ent-P4 (progesterone enantiomer); allo-Preg (allopregnanolone); ent-DHEA (DHEA enantiomer). Figure 11 shows dose-response for ent-P4 and ent- 7OHPC.

[0043] Figure 2A shows representative traces of hKir7.1 recorded from HEK293 cells in response to 10 pM of either YX-49 (green), P4 (red) or ent-P4 (black). Elicited currents were inhibited or attenuated by hKir7.1 specific inhibitor ML418 (maroon).

[0044] Figure 2B shows dose-response of hKir7.1 potentiation by either ent-P4 (black) or YX-49 (green) recorded from HEK293 as in (Fig. 2A) and calculated using the averaged current density for n cells. Data are means ± SEM.

[0045] Figure 2C shows time-course of steroid activation and washout. Averaged Kir7.1 current amplitudes from HEK293 cells as depicted in (Fig. 2A) obtained at - 80 mV were plotted against time to show a fast response to P4 (red) and its consequent fast washout. The responses to 10 pM 17-OHPC were similar in amplitude, but slower and required a much longer washout time. The time of application of the compounds to the bath solution is indicated by the bars above.

[0046] Figure 2D shows time-course of YX-49 activation acquired as described in (Fig. 2C). The responses to 10 pM 17-OHPC were stronger in amplitude, as well as required a much longer time to be inhibited by ML418. The time of application of the compounds to the bath solution is indicated by the bars above.

[0047] Figure 2E shows the fold change in iKirz.i after exposure to P4 or 17-OHPC.

[0048] DETAILED DESCRIPTION OF THE INVENTION

[0049] The present disclosure is based, at least in part, on the discovery that there are now tools to comprehensively evaluate Kir7.1 activation and its effect on RPE restoration. Kir7.1 shows excellent heterologous expression in a variety of cell types. The emerging leads could serve as starting points for lead optimization efforts towards a candidate therapeutic for dry AMD. Additionally, these compounds could be used as a research tool to interrogate function of this channel further.

[0050] Dry form of age-related macular degeneration (AMD) accounts for almost 90% of all cases and is a leading cause of blindness in people over 65 years old1. Sadly, no cure for dry AMD exists. The first two FDA-approved treatments for late- stage dry AMD- Syfovre™ and iZervay™ require repetitive intraocular injections, while the former is known for serious side effects such as retinitis vasculitis. Worldwide, AMD cases are expected to double in the next 40 years, a sharp rise from 196 million of patients in 2020 to 288 million of patients by 20402 3. In 2021 the total available market globally has reached $9.84 billion and is expected to increase by 6.9% in the next 8 years.

[0051] The earliest sign of AMD is an accumulation of cellular debris called drusen, that is a result of dysfunction of the caretaker tissue responsible for the maintenance of the retina- retinal pigment epithelium (RPE). To maintain transport of nutrients, performed controlled phagocytosis of photoreceptor outer segments (POS) to support healthy retina and maintain immune privilege of the eye, the RPE relies on a specific set of ion channels, with essential potassium channel Kir7.1 playing a critical role4'9. In the last couple of years, efforts studying the effect of steroid hormones on the regulation of epithelial ion channels led to two neurosteroids: progesterone (P4) and dehydroepiandrosterone (DHEA) that specifically, potently, and directly activate murine and human inwardly rectifying potassium channel Kir7.110 11. Kir7.1 (gene name KCNJ13) is vital for normal RPE physiology5'7 12, as loss-of-fu notion mutations in humans and mice cause profound pathophysiology of RPE, photoreceptor degradation and blindness4 8. This makes Kir7.1 a genetically and physiologically validated drug target. Production of neurosteroids, such as P4 and DHEA, is known to decline with age13, and recent research indicates that this decline may directly affect drusen formation and AMD progression14'16. However, the molecular mechanisms behind these phenomena were not completely understood, until recent work shed the light on this problem.

[0052] In the present disclosure, a strategy has been devised to apply the observation that the age-associated changes and decline in the level of neurosteroids lead to suboptimal operation of Kir7.1 in RPE, which translates into RPE pathophysiology. This pathology leads to altered transepithelial ion transport, cellular debris accumulation due to impaired phagocytosis in the subretinal space, drusen formation, inflammation, all of which eventually triggers retinopathy and AMD. Thus, to sustain healthy RPE, the function of its essential protein Kir7.1 must be maintained at a high level. Therefore, pharmacological activation of this channel could compensate for the age-related loss-of-function triggered by the changes in bioactive lipid landscape due to the declining levels of circulating neurosteroids.

[0053] The potassium channel Kir7.1 is a validated therapeutical target, well- supported by human and rodent genetics4-6'8’9. Kir7.1 belongs to a family of ion channels- the diverse group of proteins historically known to be excellent drug targets. While few Kir7.1 inhibitors have been identified17, its activators were largely unknown until the first endogenous activator of Kir7.1 - progesterone was reported10111’18. It was confirmed that recombinant human Kir7.1 and Kir7.1 expressed in murine RPE are activated by P410 and DHEA11in the identical manner and this activation is independent of G-protein signaling10(Figs. 1A-1G). These results, as well as previous publications provide strong evidence of the molecular mechanism of P4-driven control of RPE physiology and support the evidence that Kir7.1 has emerged as a promising novel therapeutic target to sustain normal RPE function. Accordingly, the present disclosure is directed to the development of Kir7.1 specific modulators and to identify specific Kir7.1 activators that lack pleotropic effect of endogenous steroids.

[0054] Among many essential RPE functions are: light energy absorption, transport of the nutrients such as glucose and vitamins from the blood to the photoreceptors, elimination of water from the subretinal space, and maintaining the immune privilege of the eye5’7’19’20. RPE ensures transepithelial transport of ions and establishes a constant ion composition in the subretinal space which is critical for maintaining constant excitability of neurosensory retina. In order to fulfill these functions, RPE relies on a specific set of ion channels and transporters, with Kir7.1 playing a critical role in this regulation. Recent reports have shown that murine and human Kir7.1 are specifically activated by P4 and DHEA, while other tested steroids, such as estradiol, testosterone, cortisol or DHEA-sulfate (DHEA-S) failed to activate Kir7.1 (Figs. 1A-1I).

[0055] The present disclosure identified three synthetic potent regulators of Kir7.1 , a synthetic progestin and FDA-approved drug for preterm labor prevention known as 17-hydroxyprogesterone-caproate (17OHP4) or Makena™, enantiomer of progesterone (enf-P4) and enantiomer of 17OHP4 (enf-Makena or YX-49) (Fig. 1 H). Each if these compounds can potentially enhance the function of RPE and restore its normal functions. However, 17OHP4 is not specific to Kir7.1 and can also interact with the genomic P4 receptor, which makes it a less desirable therapeutical compound. Enantiomers of P4 and 17OHP4, on the other hand, are more specific and will not engage with classical nuclear receptors. For example, ent-P4 does not activate human nuclear P4 receptor B and it is not a substrate, but a competitive inhibitor of human cytochromes P450c17 and P450c2121’22. ent-P4 demonstrated better affinity toward Kir7.1 with ECso (ent-P4) of 4.6 pM in comparison to affinity of P4: ECso(P4) = 11 .5 pM (Figs. 1 F, 11, and 2B), however, it has the same cell retention time as P4 (not shown) and was able to quickly wash out from the receptor (Fig. 2C). 17OHP4, however, has demonstrated a significantly longer cell retention time (Fig. 2C). Kir7.1 potentiation by 10 pM 17- OHPC was similar in strength to that of 10 pM P4; however, after drug withdrawal, the washout took five times longer with 10 pM 17-OHPC and was never fully washed out after exposure to 50 pM (Fig. 2C). The YX-49 was much more potent, ECSO(YX-49) = 520 nM (Figs. 2A-B) and kept Kir7.1 in the open state even after application of Kir7.1 inhibitor, ML418 (Fig. 2D).

[0056] The present disclosure is also based, at least in part, on the discovery that there are now tools to comprehensively evaluate Kir7.1 activation and its effect on pregnancy complications. Kir7.1 shows excellent heterologous expression in a variety of cell types. The emerging leads could serve as starting points for lead optimization efforts towards a candidate therapeutic for a pregnancy complication. Additionally, these compounds could be used as a research tool to interrogate function of this channel further.

[0057] In some embodiments, the present disclosure is directed to a compound of Formula I wherein Ri is independently selected from the group consisting of hydrogen, methyl, and ethyl; and R2 is independently selected from the group consisting of straight-chained or branched alkyl, straight-chained or branched alkenyl, and straight-chained or branched alkynyl, or a pharmaceutically acceptable salt thereof.

[0058] In some embodiments, the alkyl group has from 1 to 20 carbon atoms, from

[0059] 2 to 20 carbon atoms, from 1 to 10 carbon atoms, from 2 to 10 carbon atoms, from

[0060] 1 to 8 carbon atoms, from 2 to 8 carbon atoms, from 1 to 6 carbon atoms, from 2 to 6 carbon atoms, from 1 to 4 carbon atoms, from 2 to 4 carbon atoms, from 1 to 3 carbon atoms, or 2 or 3 carbon atoms. In some embodiments, the alkyl group has from 1 to 20 carbon atoms. In some embodiments, the alkyl group has from 2 to 20 carbon atoms. In some embodiments, the alkyl group has from 1 to 10 carbon atoms. In some embodiments, the alkyl group has from 2 to 10 carbon atoms. In some embodiments, the alkyl group has from 1 to 8 carbon atoms. In some embodiments, the alkyl group has from 2 to 8 carbon atoms. In some embodiments, the alkyl group has from 1 to 6 carbon atoms. In some embodiments, the alkyl group has from 2 to 6 carbon atoms. In some embodiments, the alkyl group has from 1 to 4 carbon atoms. In some embodiments, the alkyl group has from 2 to 4 carbon atoms. In some embodiments, the alkyl group has from 1 to 3 carbon atoms. In some embodiments, the alkyl group has 2 or 3 carbon atoms.

[0061] In some embodiments, the alkenyl group has from 2 to 10 carbon atoms, from 2 to 8 carbon atoms, from 2 to 6 carbon atoms, from 2 to 4 carbon atoms, from 3 to 10 carbon atoms, from 3 to 8 carbon atoms, from 3 to 6 carbon atoms, or

[0062] 3 or 4 carbon atoms. In some embodiments, the alkenyl group has from 2 to 10 carbon atoms. In some embodiments, the alkenyl group has from 2 to 8 carbon atoms. In some embodiments, the alkenyl group has from 2 to 6 carbon atoms. In some embodiments, the alkenyl group has from 2 to 4 carbon atoms. In some embodiments, the alkenyl group has from 3 to 10 carbon atoms. In some embodiments, the alkenyl group has from 3 to 8 carbon atoms. In some embodiments, the alkenyl group has from 3 to 6 carbon atoms. In some embodiments, the alkenyl group has 3 or 4 carbon atoms.

[0063] In some embodiments, the alkynyl group has from 2 to 10 carbon atoms, from 2 to 8 carbon atoms, from 2 to 6 carbon atoms, or from 2 to 4 carbon atoms. In some embodiments, the alkynyl group has from 2 to 10 carbon atoms. In some embodiments, the alkynyl group has from 2 to 8 carbon atoms. In some embodiments, the alkynyl group has from 2 to 6 carbon atoms. In some embodiments, the alkynyl group has from 2 to 4 carbon atoms.

[0064] In some embodiments, the compound is

[0065] In some embodiments, the present disclosure is directed to a pharmaceutical composition comprising a compound of Formula I wherein Ri is independently selected from the group consisting of hydrogen, methyl, and ethyl; R2 is independently selected from the group consisting of straight-chained or branched alkyl, straight-chained or branched alkenyl, and straight-chained or branched alkynyl, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

[0066] In some embodiments, the alkyl group has from 1 to 20 carbon atoms, from 2 to 20 carbon atoms, from 1 to 10 carbon atoms, from 2 to 10 carbon atoms, from 1 to 8 carbon atoms, from 2 to 8 carbon atoms, from 1 to 6 carbon atoms, from 2 to 6 carbon atoms, from 1 to 4 carbon atoms, from 2 to 4 carbon atoms, from 1 to 3 carbon atoms, or 2 or 3 carbon atoms. In some embodiments, the alkyl group has from 1 to 20 carbon atoms. In some embodiments, the alkyl group has from 2 to 20 carbon atoms. In some embodiments, the alkyl group has from 1 to 10 carbon atoms. In some embodiments, the alkyl group has from 2 to 10 carbon atoms. In some embodiments, the alkyl group has from 1 to 8 carbon atoms. In some embodiments, the alkyl group has from 2 to 8 carbon atoms. In some embodiments, the alkyl group has from 1 to 6 carbon atoms. In some embodiments, the alkyl group has from 2 to 6 carbon atoms. In some embodiments, the alkyl group has from 1 to 4 carbon atoms. In some embodiments, the alkyl group has from 2 to 4 carbon atoms. In some embodiments, the alkyl group has from 1 to 3 carbon atoms. In some embodiments, the alkyl group has 2 or 3 carbon atoms.

[0067] In some embodiments, the alkenyl group has from 2 to 10 carbon atoms, from 2 to 8 carbon atoms, from 2 to 6 carbon atoms, from 2 to 4 carbon atoms, from 3 to 10 carbon atoms, from 3 to 8 carbon atoms, from 3 to 6 carbon atoms, or 3 or 4 carbon atoms. In some embodiments, the alkenyl group has from 2 to 10 carbon atoms. In some embodiments, the alkenyl group has from 2 to 8 carbon atoms. In some embodiments, the alkenyl group has from 2 to 6 carbon atoms. In some embodiments, the alkenyl group has from 2 to 4 carbon atoms. In some embodiments, the alkenyl group has from 3 to 10 carbon atoms. In some embodiments, the alkenyl group has from 3 to 8 carbon atoms. In some embodiments, the alkenyl group has from 3 to 6 carbon atoms. In some embodiments, the alkenyl group has 3 or 4 carbon atoms.

[0068] In some embodiments, the alkynyl group has from 2 to 10 carbon atoms, from 2 to 8 carbon atoms, from 2 to 6 carbon atoms, or from 2 to 4 carbon atoms. In some embodiments, the alkynyl group has from 2 to 10 carbon atoms. In some embodiments, the alkynyl group has from 2 to 8 carbon atoms. In some embodiments, the alkynyl group has from 2 to 6 carbon atoms. In some embodiments, the alkynyl group has from 2 to 4 carbon atoms.

[0069] In some embodiments, the compound is

[0070] In some embodiments, the pharmaceutically acceptable carrier is a saline solution or an eye drop formulation. In some embodiments, the pharmaceutical composition further comprises (2-hydroxypropyl)-p-cyclodextrin.

[0071] In some embodiments, the pharmaceutically acceptable carrier is a saline solution, ethanol-based solution, DMSO-based solution, or a mixture with mineral oils, or similar formulation. In some embodiments, the pharmaceutically acceptable carrier is a saline solution. In some embodiments, the pharmaceutically acceptable carrier is an ethanol-based solution. In some embodiments, the pharmaceutically acceptable carrier is a DMSO-based solution. In some embodiments, the pharmaceutically acceptable carrier is a mixture with mineral oils.

[0072] In some embodiments, the present disclosure is directed to a method of preventing or treating age-related macular degeneration (AMD) comprising administering a therapeutically effective amount of a compound of Formula I wherein Ri is independently selected from the group consisting of hydrogen, methyl, and ethyl; and R2 is independently selected from the group consisting of straight-chained or branched alkyl, straight-chained or branched alkenyl, and straight-chained or branched alkynyl, or a pharmaceutically acceptable salt thereof.

[0073] In some embodiments, the alkyl group has from 1 to 20 carbon atoms, from 2 to 20 carbon atoms, from 1 to 10 carbon atoms, from 2 to 10 carbon atoms, from 1 to 8 carbon atoms, from 2 to 8 carbon atoms, from 1 to 6 carbon atoms, from 2 to 6 carbon atoms, from 1 to 4 carbon atoms, from 2 to 4 carbon atoms, from 1 to 3 carbon atoms, or 2 or 3 carbon atoms. In some embodiments, the alkyl group has from 1 to 20 carbon atoms. In some embodiments, the alkyl group has from 2 to 20 carbon atoms. In some embodiments, the alkyl group has from 1 to 10 carbon atoms. In some embodiments, the alkyl group has from 2 to 10 carbon atoms. In some embodiments, the alkyl group has from 1 to 8 carbon atoms. In some embodiments, the alkyl group has from 2 to 8 carbon atoms. In some embodiments, the alkyl group has from 1 to 6 carbon atoms. In some embodiments, the alkyl group has from 2 to 6 carbon atoms. In some embodiments, the alkyl group has from 1 to 4 carbon atoms. In some embodiments, the alkyl group has from 2 to 4 carbon atoms. In some embodiments, the alkyl group has from 1 to 3 carbon atoms. In some embodiments, the alkyl group has 2 or 3 carbon atoms.

[0074] In some embodiments, the alkenyl group has from 2 to 10 carbon atoms, from 2 to 8 carbon atoms, from 2 to 6 carbon atoms, from 2 to 4 carbon atoms, from 3 to 10 carbon atoms, from 3 to 8 carbon atoms, from 3 to 6 carbon atoms, or 3 or 4 carbon atoms. In some embodiments, the alkenyl group has from 2 to 10 carbon atoms. In some embodiments, the alkenyl group has from 2 to 8 carbon atoms. In some embodiments, the alkenyl group has from 2 to 6 carbon atoms. In some embodiments, the alkenyl group has from 2 to 4 carbon atoms. In some embodiments, the alkenyl group has from 3 to 10 carbon atoms. In some embodiments, the alkenyl group has from 3 to 8 carbon atoms. In some embodiments, the alkenyl group has from 3 to 6 carbon atoms. In some embodiments, the alkenyl group has 3 or 4 carbon atoms.

[0075] In some embodiments, the alkynyl group has from 2 to 10 carbon atoms, from 2 to 8 carbon atoms, from 2 to 6 carbon atoms, or from 2 to 4 carbon atoms. In some embodiments, the alkynyl group has from 2 to 10 carbon atoms. In some embodiments, the alkynyl group has from 2 to 8 carbon atoms. In some embodiments, the alkynyl group has from 2 to 6 carbon atoms. In some embodiments, the alkynyl group has from 2 to 4 carbon atoms.

[0076] In some embodiments, the compound is

[0077] In some embodiments, the age-related macular degeneration (AMD) is dry AMD.

[0078] In some embodiments, the administering a therapeutically effective amount of the composition comprises administering the composition by intravitreal injection or intracameral injection or via eye drops. In some embodiments, the administering a therapeutically effective amount of the composition comprises administering the composition by intravitreal injection. In some embodiments, the administering a therapeutically effective amount of the composition comprises administering the composition by intracameral injection. In some embodiments, the administering a therapeutically effective amount of the composition comprises administering the composition via eye drops.

[0079] In some embodiments, the compound, or pharmaceutically acceptable salt thereof is administered at a concentration of from about 10 nM to about 100 pM.

[0080] In some embodiments, the compound is

[0081] In some embodiments, the present disclosure is directed to a method of preventing or treating age-related macular degeneration (AMD) comprising administering a therapeutically effective amount of a composition comprising ent- progesterone, or a pharmaceutically acceptable salt thereof.

[0082] In some embodiments, the enf-progesterone composition further comprises a saline solution. In some embodiments, the enf-progesterone composition further comprises (2-hydroxypropyl)-[3-cyclodextrin.

[0083] In some embodiments, the age-related macular degeneration (AMD) is dry

[0084] AMD.

[0085] In some embodiments, the administering a therapeutically effective amount of the ent-progesterone composition comprises administering the enf-progesterone composition by intravitreal injection or intracameral injection or via eye drops. In some embodiments, the administering a therapeutically effective amount of the enf-progesterone composition comprises administering the enf-progesterone composition by intravitreal injection. In some embodiments, the administering a therapeutically effective amount of the ent-progesterone composition comprises administering the ent-progesterone composition by intracameral injection. In some embodiments, the administering a therapeutically effective amount of the ent- progesterone composition comprises administering the enf-progesterone composition via eye drops.

[0086] In some embodiments, the enf-progesterone composition comprises ent- progesterone, or a pharmaceutically acceptable salt thereof, in a concentration of from about 10 nM to about 100 pM.

[0087] In some embodiments, the present disclosure is directed to a method of preventing or treating a pregnancy complication comprising administering a therapeutically effective amount of a compound of Formula I wherein Ri is independently selected from the group consisting of hydrogen, methyl, and ethyl; and R2 is independently selected from the group consisting of straight-chained or branched alkyl, straight-chained or branched alkenyl, and straight-chained or branched alkynyl, or a pharmaceutically acceptable salt thereof.

[0088] In some embodiments, the alkyl group has from 1 to 20 carbon atoms, from 2 to 20 carbon atoms, from 1 to 10 carbon atoms, from 2 to 10 carbon atoms, from 1 to 8 carbon atoms, from 2 to 8 carbon atoms, from 1 to 6 carbon atoms, from 2 to 6 carbon atoms, from 1 to 4 carbon atoms, from 2 to 4 carbon atoms, from 1 to 3 carbon atoms, or 2 or 3 carbon atoms. In some embodiments, the alkyl group has from 1 to 20 carbon atoms. In some embodiments, the alkyl group has from 2 to 20 carbon atoms. In some embodiments, the alkyl group has from 1 to 10 carbon atoms. In some embodiments, the alkyl group has from 2 to 10 carbon atoms. In some embodiments, the alkyl group has from 1 to 8 carbon atoms. In some embodiments, the alkyl group has from 2 to 8 carbon atoms. In some embodiments, the alkyl group has from 1 to 6 carbon atoms. In some embodiments, the alkyl group has from 2 to 6 carbon atoms. In some embodiments, the alkyl group has from 1 to 4 carbon atoms. In some embodiments, the alkyl group has from 2 to 4 carbon atoms. In some embodiments, the alkyl group has from 1 to 3 carbon atoms. In some embodiments, the alkyl group has 2 or 3 carbon atoms.

[0089] In some embodiments, the alkenyl group has from 2 to 10 carbon atoms, from 2 to 8 carbon atoms, from 2 to 6 carbon atoms, from 2 to 4 carbon atoms, from 3 to 10 carbon atoms, from 3 to 8 carbon atoms, from 3 to 6 carbon atoms, or 3 or 4 carbon atoms. In some embodiments, the alkenyl group has from 2 to 10 carbon atoms. In some embodiments, the alkenyl group has from 2 to 8 carbon atoms. In some embodiments, the alkenyl group has from 2 to 6 carbon atoms. In some embodiments, the alkenyl group has from 2 to 4 carbon atoms. In some embodiments, the alkenyl group has from 3 to 10 carbon atoms. In some embodiments, the alkenyl group has from 3 to 8 carbon atoms. In some embodiments, the alkenyl group has from 3 to 6 carbon atoms. In some embodiments, the alkenyl group has 3 or 4 carbon atoms.

[0090] In some embodiments, the alkynyl group has from 2 to 10 carbon atoms, from 2 to 8 carbon atoms, from 2 to 6 carbon atoms, or from 2 to 4 carbon atoms. In some embodiments, the alkynyl group has from 2 to 10 carbon atoms. In some embodiments, the alkynyl group has from 2 to 8 carbon atoms. In some embodiments, the alkynyl group has from 2 to 6 carbon atoms. In some embodiments, the alkynyl group has from 2 to 4 carbon atoms.

[0091] In some embodiments, the compound is

[0092] In some embodiments, the pregnancy complication is selected from preterm labor and preeclampsia.

[0093] In some embodiments, the administering a therapeutically effective amount of the composition comprises administering the composition by intramuscular, or intravenous, or intraperitoneal injections or delivered topically. In some embodiments, the administering a therapeutically effective amount of the composition comprises administering the composition by intramuscular injection. In some embodiments, the administering a therapeutically effective amount of the composition comprises administering the composition by intravenous injection. In some embodiments, the administering a therapeutically effective amount of the composition comprises administering the composition by intraperitoneal injection. In some embodiments, the administering a therapeutically effective amount of the composition comprises administering the composition topically.

[0094] In some embodiments, the compound, or pharmaceutically acceptable salt thereof is administered at a concentration of from about 10 nM to about 100 pM.

[0095] In some embodiments, the compound is

[0096] In some embodiments, the present disclosure is directed to a method of preventing or treating a pregnancy complication comprising administering a therapeutically effective amount of a composition comprising enf-progesterone, or a pharmaceutically acceptable salt thereof.

[0097] In some embodiments, the enf-progesterone composition further comprises a saline solution, an ethanol-based solution, a DMSO-based solution, or a mixture with mineral oils, or similar formulation. In some embodiments, the ent- progesterone composition further comprises a saline solution. In some embodiments, the enf-progesterone composition further comprises an ethanol- based solution. In some embodiments, the enf-progesterone composition further comprises a DMSO-based solution. In some embodiments, the ent-prog esterone composition further comprises a mixture with mineral oils. In some embodiments, the ent-progesterone composition further comprises (2-hydroxypropyl)-P- cyclodextrin.

[0098] In some embodiments, the pregnancy complication is selected from preterm labor and preeclampsia.

[0099] In some embodiments, the administering a therapeutically effective amount of the enf-progesterone composition comprises administering the ent-progesterone composition by intramuscular, or intravenous, or intraperitoneal injections or delivered topically. In some embodiments, the administering a therapeutically effective amount of the ent-progesterone composition comprises administering the enf-progesterone composition by intramuscular injection. In some embodiments, the administering a therapeutically effective amount of the ent-progesterone composition comprises administering the ent-progesterone composition by intravenous injection. In some embodiments, the administering a therapeutically effective amount of the ent-progesterone composition comprises administering the enf-progesterone composition by intraperitoneal injection. In some embodiments, the administering a therapeutically effective amount of the ent-progesterone composition comprises administering the ent-progesterone composition topically.

[0100] In some embodiments, the ent-progesterone composition comprises ent- progesterone, or a pharmaceutically acceptable salt thereof, in a concentration of from about 10 nM to about 100 pM.

[0101] In some embodiments, the present disclosure is directed to a method of preparing ent-[17a-hydroxyprogesterone caproate] (6) comprising the steps of:

[0102] 1 ) converting ent-testosterone to enf-androstenedione (1 );

[0103] 2) converting enf-androstenedione (1 ) to ent-[(17a)-17-hydroxy-3- oxoandrost-4-ene-17-carbo nitrile] (2);

[0104] 3) converting enf-[(17a)-17-hydroxy-3-oxoandrost-4-ene-17-carbonitrile] (2) to ent-[17a-3,3-(1 ,2-ethanediylbis(oxy))-17-hydroxyandrost-5-ene-17- carbonitrile] (3);

[0105] 4) converting ent-[17a-3,3-(1 ,2-ethanediylbis(oxy))-17-hydroxyandrost- 5-ene-17-carbonitrile] (3) to enf-[(17a)-3,3-(1 ,2-ethanediylbis(oxy))-17-(1- ethoxyethoxy)-androst-5-ene-17-carbonitrile] (4);

[0106] 5) converting ent-[(17a)-3,3-(1 ,2-ethanediylbis(oxy))-17-(1- ethoxyethoxy)-androst-5-ene-17-carbonitrile] (4) to enf-[17o-hydroxyprogesterone] (5);

[0107] 6) converting ent-[17a-hydroxyprogesterone] (5) to enf-[17a- hydroxy prog esterone caproate] (6).

[0108] In some embodiments, numbers expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and so forth, used to describe and claim certain embodiments of the present disclosure are to be understood as being modified in some instances by the term “about.” In some embodiments, the term “about” is used to indicate that a value includes the standard deviation of the mean for the device or method being employed to determine the value. In some embodiments, the numerical parameters set forth in the written description and attached claims are approximations that vary depending upon the desired properties sought to be obtained by a particular embodiment. In some embodiments, the numerical parameters are be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the present disclosure are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable. The numerical values presented in some embodiments of the present disclosure may contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements. The recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein.

[0109] In some embodiments, the terms “a” and “an” and “the” and similar references used in the context of describing a particular embodiment (especially in the context of certain of the following claims) are construed to cover both the singular and the plural, unless specifically noted otherwise. In some embodiments, the term “or” as used herein, including the claims, is used to mean “and / or” unless explicitly indicated to refer to alternatives only or to refer to the alternatives that are mutually exclusive.

[0110] The terms “comprise,” “have” and “include” are open-ended linking verbs. Any forms or tenses of one or more of these verbs, such as “comprises,” “comprising,” “has,” “having,” “includes” and “including,” are also open-ended. For example, any method that “comprises,” “has” or “includes” one or more steps is not limited to possessing only those one or more steps and may also cover other unlisted steps. Similarly, any composition or device that “comprises,” “has” or “includes” one or more features is not limited to possessing only those one or more features and may cover other unlisted features.

[0111] All methods described herein are performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g. “such as”) provided with respect to certain embodiments herein is intended merely to better illuminate the present disclosure and does not pose a limitation on the scope of the present disclosure otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the present disclosure.

[0112] Groupings of alternative elements or embodiments of the present disclosure disclosed herein are not to be construed as limitations. Each group member is referred to and claimed individually or in any combination with other members of the group or other elements found herein. One or more members of a group are included in, or deleted from, a group for reasons of convenience or patentability. When any such inclusion or deletion occurs, the specification is herein deemed to contain the group as modified thus fulfilling the written description of all Markush groups used in the appended claims.

[0113] To facilitate the understanding of the embodiments described herein, a number of terms are defined below. The terms defined herein have meanings as commonly understood by a person of ordinary skill in the areas relevant to the present disclosure. Terms such as “a,” “an,” and “the” are not intended to refer to only a singular entity, but rather include the general class of which a specific example may be used for illustration. The terminology herein is used to describe specific embodiments of the disclosure, but their usage does not delimit the disclosure, except as outlined in the claims.

[0114] All of the compositions and / or methods disclosed and claimed herein may be made and / or executed without undue experimentation in light of the present disclosure. While the compositions and methods of this disclosure have been described in terms of the embodiments included herein, it will be apparent to those of ordinary skill in the art that variations may be applied to the compositions and / or methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit, and scope of the disclosure. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope, and concept of the disclosure as defined by the appended claims.

[0115] This written description uses examples to disclose the disclosure, including the best mode, and also to enable any person skilled in the art to practice the disclosure, including making and using any devices or systems and performing any incorporated methods. The patentable scope of the disclosure is defined by the claims, and may include other examples that occur to those skilled in the art. Such other examples are intended to be within the scope of the claims if they have structural elements that do not differ from the literal language of the claims, or if they include equivalent structural elements with insubstantial differences from the literal language of the claims.

[0116] R groups can be optionally substituted with one or more groups independently selected from the group consisting of hydroxyl; Ci- alkyl hydroxyl; amine; Ci- carboxylic acid; Ci- carboxyl; straight chain or branched Ci- alkyl, optionally containing unsaturation; a C2-wcycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom; straight chain or branched C1-1 oal ky I amine; heterocyclyl; heterocyclic amine; and aryl comprising a phenyl; heteroaryl containing from 1 to 4 N, O, or S atoms; unsubstituted phenyl ring; substituted phenyl ring; unsubstituted heterocyclyl; and substituted heterocyclyl, wherein the unsubstituted phenyl ring or substituted phenyl ring can be optionally substituted with one or more groups independently selected from the group consisting of hydroxyl; Ci- alkyl hydroxyl; amine; Ci- carboxylic acid; Ci-wcarboxyl; straight chain or branched Ci-ioalkyl, optionally containing unsaturation; straight chain or branched Ci-walkyl amine, optionally containing unsaturation; a C2-wcycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom; straight chain or branched Ci -walkyl amine; heterocyclyl; heterocyclic amine; aryl comprising a phenyl; and heteroaryl containing from 1 to 4 N, O, or S atoms; and the unsubstituted heterocyclyl or substituted heterocyclyl can be optionally substituted with one or more groups independently selected from the group consisting of hydroxyl; Ci alkyl hydroxyl; amine; Ci- carboxylic acid; Ci- carboxyl; straight chain or branched Ci walkyl, optionally containing unsaturation; straight chain or branched Ci-walkyl amine, optionally containing unsaturation; a C2-wcycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom; heterocyclyl; straight chain or branched Ci-walkyl amine; heterocyclic amine; and aryl comprising a phenyl; and heteroaryl containing from 1 to 4 N, O, or S atoms. Any of the above can be further optionally substituted.

[0117] The term “hydroxyl”, as used herein, unless otherwise indicated, can include -OH. The “hydroxyl” can be optionally substituted.

[0118] The term “aryl”, as used herein, unless otherwise indicated, includes a carbocyclic aromatic group. Examples of aryl groups include, but are not limited to, phenyl, benzyl, naphthyl, or anthracenyl. The “aryl” can be optionally substituted.

[0119] The terms “amine” and “amino”, as used herein, unless otherwise indicated, include a functional group that contains a nitrogen atom with a lone pair of electrons and wherein one or more hydrogen atoms have been replaced by a substituent such as, but not limited to, an alkyl group or an aryl group. The “amine” or “amino” group can be optionally substituted.

[0120] The term “alkyl”, as used herein, unless otherwise indicated, can include saturated monovalent hydrocarbon radicals having straight or branched moieties, such as but not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, octyl groups, etc. Representative straight-chain lower alkyl groups include, but are not limited to, -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, -n-hexyl, -n-heptyl and -n-octyl; while branched lower alkyl groups include, but are not limited to, -isopropyl, -sec-butyl, - isobutyl, -tert-butyl, -isopentyl, 2-methylbutyl, 2-methylpentyl, 3-methylpentyl, 2,2- dimethylbutyl, 2,3-dimethylbutyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, 3,3- dimethylpentyl, 2,3,4-trimethylpentyl, 3-methylhexyl, 2,2-dimethylhexyl, 2,4- dimethylhexyl, 2,5-dimethylhexyl, 3,5-dimethylhexyl, 2,4-dimethylpentyl, 2- methylheptyl, 3-methylheptyl, unsaturated C1-10 alkyls include, but are not limited to, -vinyl, -allyl, -1-butenyl, -2-butenyl, -isobutylenyl, -1-pentenyl, -2-pentenyl, -3- methyl-1-butenyl, -2-methyl-2-butenyl, -2,3-dimethyl-2-butenyl, 1-hexyl, 2-hexyl, 3- hexyl, -acetylenyl, -propynyl, -1 -butynyl, -2-butynyl, -1 -pentynyl, -2-pentynyl, or -3- methyl-1 butynyl. An alkyl can be saturated, partially saturated, or unsaturated. The “alkyl” can be optionally substituted.

[0121] The term “carboxyl”, as used herein, unless otherwise indicated, can include a functional group consisting of a carbon atom double bonded to an oxygen atom and single bonded to a hydroxyl group (-COOH). The “carboxyl” can be optionally substituted.

[0122] The term “alkenyl”, as used herein, unless otherwise indicated, can include alkyl moieties having at least one carbon-carbon double bond wherein alkyl is as defined above and including E and Z isomers of said alkenyl moiety. An alkenyl can be partially saturated or unsaturated. The “alkenyl” can be optionally substituted.

[0123] The term “alkynyl”, as used herein, unless otherwise indicated, can include alkyl moieties having at least one carbon-carbon triple bond wherein alkyl is as defined above. An alkynyl can be partially saturated or unsaturated. The “alkynyl” can be optionally substituted.

[0124] The term “cycloalkyl”, as used herein, unless otherwise indicated, can include an aromatic, non-aromatic, saturated, partially saturated, or unsaturated, monocyclic or fused, spiro or unfused bicyclic or tricyclic hydrocarbon referred to herein containing a total of from 1 to 10 carbon atoms (e.g., 1 or 2 carbon atoms if there are other heteroatoms in the ring), preferably 3 to 8 ring carbon atoms. Examples of cycloalkyls include, but are not limited to, C3-10 cycloalkyl groups include, but are not limited to, -cyclopropyl, -cyclobutyl, -cyclopentyl, - cyclopentadienyl, -cyclohexyl, -cyclohexenyl, -1 ,3-cyclohexadienyl, -1 ,4- cyclohexadienyl, -cycloheptyl, -1 ,3-cycloheptadienyl, -1 ,3,5-cycloheptatrienyl, - cyclooctyl, and -cyclooctadienyl. The term “cycloalkyl” also can include -lower alkyl-cycloalkyl, wherein lower alkyl and cycloalkyl are as defined herein. Examples of -lower alkyl-cycloalkyl groups include, but are not limited to, -CH2- cyclopropyl, -CFE-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclopentadienyl, -CH2- cyclohexyl, -CH2-cycloheptyl, or -CH2-cyclooctyl. The “cycloalkyl” can be optionally substituted. A “cycloheteroalkyl”, as used herein, unless otherwise indicated, can include any of the above with a carbon substituted with a heteroatom (e.g., O, S, N).

[0125] The term “heterocyclic” or “heteroaryl”, as used herein, unless otherwise indicated, can include an aromatic or non-aromatic cycloalkyl in which one to four of the ring carbon atoms are independently replaced with a heteroatom from the group consisting of O, S and N. Representative examples of a heterocycle include, but are not limited to, benzofuranyl, benzothiophene, indolyl, benzopyrazolyl, coumarinyl, isoquinolinyl, pyrrolyl, pyrrolidinyl, thiophenyl, furanyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, quinolinyl, pyrimidinyl, pyridinyl, pyridonyl, pyrazinyl, pyridazinyl, isothiazolyl, isoxazolyl, (1 ,4)-dioxane, (1 ,3)-dioxolane, 4,5-dihydro-1 H- imidazolyl, or tetrazolyl. Heterocycles can be substituted or unsubstituted. Heterocycles can also be bonded at any ring atom (i.e. , at any carbon atom or heteroatom of the heterocyclic ring). A heterocyclic can be saturated, partially saturated, or unsaturated. The “hetreocyclic” can be optionally substituted.

[0126] The term “solvate” is intended to mean a solvate form of a specified compound that retains the effectiveness of such a compound. Examples of solvates include compounds of the invention in combination with, for example: water, isopropanol, ethanol, methanol, dimethylsulfoxide (DMSO), ethyl acetate, acetic acid, or ethanolamine.

[0127] The term “mmol”, as used herein, is intended to mean millimole. The term “equiv”, as used herein, is intended to mean equivalent. The term “mL”, as used herein, is intended to mean milliliter. The term “g”, as used herein, is intended to mean gram. The term “kg”, as used herein, is intended to mean kilogram. The term “pg”, as used herein, is intended to mean micrograms. The term “h”, as used herein, is intended to mean hour. The term “min”, as used herein, is intended to mean minute. The term “M”, as used herein, is intended to mean molar. The term "pL", as used herein, is intended to mean microliter. The term “pM”, as used herein, is intended to mean micromolar. The term “nM”, as used herein, is intended to mean nanomolar. The term “N”, as used herein, is intended to mean normal. The term “amu”, as used herein, is intended to mean atomic mass unit. The term “°C”, as used herein, is intended to mean degree Celsius. The term “wt / wt”, as used herein, is intended to mean weight / weight. The term “v / v”, as used herein, is intended to mean volume / volume. The term “MS”, as used herein, is intended to mean mass spectroscopy. The term “HPLC”, as used herein, is intended to mean high-performance liquid chromatography. The term “RT”, as used herein, is intended to mean room temperature. The term "e.g.", as used herein, is intended to mean example. The term “N / A”, as used herein, is intended to mean not tested.

[0128] As used herein, the expression “pharmaceutically acceptable salt” refers to pharmaceutically acceptable organic or inorganic salts of a compound of the invention. Preferred salts include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, or pamoate (i.e., 1 ,1 '- methylene-bis-(2-hydroxy-3-naphthoate)) salts. A pharmaceutically acceptable salt may involve the inclusion of another molecule such as an acetate ion, a succinate ion, or other counterion. The counterion may be any organic or inorganic moiety that stabilizes the charge on the parent compound. Furthermore, a pharmaceutically acceptable salt may have more than one charged atom in its structure. Instances where multiple charged atoms are part of the pharmaceutically acceptable salt can have multiple counterions. Hence, a pharmaceutically acceptable salt can have one or more charged atoms and / or one or more counterion. As used herein, the expression “pharmaceutically acceptable solvate” refers to an association of one or more solvent molecules and a compound of the invention. Examples of solvents that form pharmaceutically acceptable solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine. As used herein, the expression “pharmaceutically acceptable hydrate” refers to a compound of the invention, or a salt thereof, that further can include a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.

[0129] FORMULATION

[0130] The agents and compositions described herein can be formulated by any conventional manner using one or more pharmaceutically acceptable carriers or excipients as described in, for example, Remington’s Pharmaceutical Sciences (A.R. Gennaro, Ed.), 21 st edition, ISBN: 0781746736 (2005), incorporated herein by reference in its entirety. Such formulations will contain a therapeutically effective amount of a biologically active agent described herein, which can be in purified form, together with a suitable amount of carrier so as to provide the form for proper administration to the subject.

[0131] The term "formulation" refers to preparing a drug in a form suitable for administration to a subject, such as a human. Thus, a "formulation" can include pharmaceutically acceptable excipients, including diluents or carriers.

[0132] The term "pharmaceutically acceptable" as used herein can describe substances or components that do not cause unacceptable losses of pharmacological activity or unacceptable adverse side effects. Examples of pharmaceutically acceptable ingredients can be those having monographs in United States Pharmacopeia (USP 29) and National Formulary (NF 24), United States Pharmacopeial Convention, Inc, Rockville, Maryland, 2005 ("USP / NF"), or a more recent edition, and the components listed in the continuously updated Inactive Ingredient Search online database of the FDA. Other useful components that are not described in the USP / NF, etc. may also be used.

[0133] The term “pharmaceutically acceptable excipient,” as used herein, can include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic, or absorption-delaying agents. The use of such media and agents for pharmaceutically active substances is well known in the art (see generally Remington’s Pharmaceutical Sciences (A.R. Gennaro, Ed.), 21 st edition, ISBN: 0781746736 (2005)). Except insofar as any conventional media or agent is incompatible with an active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.

[0134] A "stable" formulation or composition can refer to a composition having sufficient stability to allow storage at a convenient temperature, such as between about 0 °C and about 60 °C, for a commercially reasonable period of time, such as at least about one day, at least about one week, at least about one month, at least about three months, at least about six months, at least about one year, or at least about two years. The formulation should suit the mode of administration. The agents of use with the current disclosure can be formulated by known methods for administration to a subject using several routes which include, but are not limited to, parenteral, pulmonary, oral, topical, intradermal, intratumoral, intranasal, inhalation (e.g., in an aerosol), implanted, intramuscular, intraperitoneal, intravenous, intrathecal, intracranial, intracerebroventricular, subcutaneous, intranasal, epidural, intrathecal, ophthalmic, transdermal, buccal, and rectal. The individual agents may also be administered in combination with one or more additional agents or together with other biologically active or biologically inert agents. Such biologically active or inert agents may be in fluid or mechanical communication with the agent(s) or attached to the agent(s) by ionic, covalent, Van der Waals, hydrophobic, hydrophilic, or other physical forces.

[0135] Controlled-release (or sustained-release) preparations may be formulated to extend the activity of the agent(s) and reduce dosage frequency. Controlled- release preparations can also be used to effect the time of onset of action or other characteristics, such as blood levels of the agent, and consequently affect the occurrence of side effects. Controlled-release preparations may be designed to initially release an amount of an agent(s) that produces the desired therapeutic effect, and gradually and continually release other amounts of the agent to maintain the level of therapeutic effect over an extended period of time. In order to maintain a near-constant level of an agent in the body, the agent can be released from the dosage form at a rate that will replace the amount of the agent being metabolized or excreted from the body. The controlled-release of an agent may be stimulated by various inducers, e.g., change in pH, change in temperature, enzymes, water, or other physiological conditions or molecules.

[0136] Agents or compositions described herein can also be used in combination with other therapeutic modalities, as described further below. Thus, in addition to the therapies described herein, one may also provide to the subject other therapies known to be efficacious for the treatment of the disease, disorder, or condition.

[0137] THERAPEUTIC METHODS

[0138] Also provided is a process of treating or preventing age-related macular degeneration (AMD) in a subject in need of administration of a therapeutically effective amount of an enantiomeric steroid modulator.

[0139] Methods described herein are generally performed on a subject in need thereof. A subject in need of the therapeutic methods described herein can be a subject having, diagnosed with, suspected of having, or at risk for developing age- related macular degeneration (AMD). A determination of the need for treatment will typically be assessed by a history, physical exam, or diagnostic tests consistent with the disease or condition at issue. Diagnosis of the various conditions treatable by the methods described herein is within the skill of the art. The subject can be an animal subject, including a mammal, such as horses, cows, dogs, cats, sheep, pigs, mice, rats, monkeys, hamsters, guinea pigs, and humans or chickens. For example, the subject can be a human subject.

[0140] Generally, a safe and effective amount of an enantiomeric steroid modulator is, for example, an amount that would cause the desired therapeutic effect in a subject while minimizing undesired side effects. In various embodiments, an effective amount of an enantiomeric steroid modulator described herein can substantially inhibit age-related macular degeneration (AMD), slow the progress of age-related macular degeneration (AMD), or limit the development of age-related macular degeneration (AMD).

[0141] According to the methods described herein, administration can be intravitreal injection, intracameral injection, or via eye drops.

[0142] When used in the treatments described herein, a therapeutically effective amount of an enantiomeric steroid modulator can be employed in pure form or, where such forms exist, in pharmaceutically acceptable salt form and with or without a pharmaceutically acceptable excipient. For example, the compounds of the present disclosure can be administered, at a reasonable benefit / risk ratio applicable to any medical treatment, in a sufficient amount to treat age-related macular degeneration (AMD).

[0143] The amount of a composition described herein that can be combined with a pharmaceutically acceptable carrier to produce a single dosage form will vary depending upon the subject or host treated and the particular mode of administration. It will be appreciated by those skilled in the art that the unit content of agent contained in an individual dose of each dosage form need not in itself constitute a therapeutically effective amount, as the necessary therapeutically effective amount could be reached by administration of a number of individual doses.

[0144] Toxicity and therapeutic efficacy of compositions described herein can be determined by standard pharmaceutical procedures in cell cultures or experimental animals for determining the LDso (the dose lethal to 50% of the population) and the EDso, (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index that can be expressed as the ratio LD50 / ED50, where larger therapeutic indices are generally understood in the art to be optimal.

[0145] The specific therapeutically effective dose level for any particular subject will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the subject; the time of administration; the route of administration; the rate of excretion of the composition employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts (see e.g., Koda-Kimble et al. (2004) Applied Therapeutics: The Clinical Use of Drugs, Lippincott Williams & Wilkins, ISBN 0781748453; Winter (2003) Basic Clinical Pharmacokinetics, 4thed., Lippincott Williams & Wilkins, ISBN 0781741475; Sharqel (2004) Applied Biopharmaceutics & Pharmacokinetics, McGraw-Hill / Appleton & Lange, ISBN 0071375503). For example, it is well within the skill of the art to start doses of the composition at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. If desired, the effective daily dose may be divided into multiple doses for purposes of administration. Consequently, single-dose compositions may contain such amounts or submultiples thereof to make up the daily dose. It will be understood, however, that the total daily usage of the compounds and compositions of the present disclosure will be decided by an attending physician within the scope of sound medical judgment.

[0146] Again, each of the states, diseases, disorders, and conditions, described herein, as well as others, can benefit from compositions and methods described herein. Generally, treating a state, disease, disorder, or condition includes preventing, reversing, or delaying the appearance of clinical symptoms in a mammal that may be afflicted with or predisposed to the state, disease, disorder, or condition but does not yet experience or display clinical or subclinical symptoms thereof. Treating can also include inhibiting the state, disease, disorder, or condition, e.g., arresting or reducing the development of the disease or at least one clinical or subclinical symptom thereof. Furthermore, treating can include relieving the disease, e.g., causing regression of the state, disease, disorder, or condition or at least one of its clinical or subclinical symptoms. A benefit to a subject to be treated can be either statistically significant or at least perceptible to the subject or to a physician.

[0147] Administration of an enantiomeric steroid modulator can occur as a single event or over a time course of treatment. For example, an enantiomeric steroid modulator can be administered daily, weekly, bi-weekly, or monthly. For treatment of acute conditions, the time course of treatment will usually be at least several days. Certain conditions could extend treatment from several days to several weeks. For example, treatment could extend over one week, two weeks, or three weeks. For more chronic conditions, treatment could extend from several weeks to several months or even a year or more.

[0148] Treatment in accord with the methods described herein can be performed prior to, concurrent with, or after conventional treatment modalities for age-related macular degeneration (AMD).

[0149] An enantiomeric steroid modulator can be administered simultaneously or sequentially with another agent, such as an antibiotic, an anti-inflammatory, or another agent. For example, an enantiomeric steroid modulator can be administered simultaneously with another agent, such as an antibiotic or an antiinflammatory. Simultaneous administration can occur through the administration of separate compositions, each containing one or more of an enantiomeric steroid modulator, an antibiotic, an anti-inflammatory, or another agent. Simultaneous administration can occur through the administration of one composition containing two or more of an enantiomeric steroid modulator, an antibiotic, an antiinflammatory, or another agent. An enantiomeric steroid modulator can be administered sequentially with an antibiotic, an anti-inflammatory, or another agent. For example, an enantiomeric steroid modulator can be administered before or after administration of an antibiotic, an anti-inflammatory, or another agent.

[0150] Also provided is a process of treating or preventing a pregnancy complication in a subject in need of administration of a therapeutically effective amount of an enantiomeric steroid modulator.

[0151] Methods described herein are generally performed on a subject in need thereof. A subject in need of the therapeutic methods described herein can be a subject having, diagnosed with, suspected of having, or at risk for developing a pregnancy complication. A determination of the need for treatment will typically be assessed by a history, physical exam, or diagnostic tests consistent with the disease or condition at issue. Diagnosis of the various conditions treatable by the methods described herein is within the skill of the art. The subject can be an animal subject, including a mammal, such as horses, cows, dogs, cats, sheep, pigs, mice, rats, monkeys, hamsters, guinea pigs, and humans or chickens. For example, the subject can be a human subject.

[0152] Generally, a safe and effective amount of an enantiomeric steroid modulator is, for example, an amount that would cause the desired therapeutic effect in a subject while minimizing undesired side effects. In various embodiments, an effective amount of an enantiomeric steroid modulator described herein can substantially inhibit a pregnancy complication, slow the progress of a pregnancy complication, or limit the development of a pregnancy complication.

[0153] According to the methods described herein, administration can be intramuscular, or intravenous, or intraperitoneal injections or delivered topically.

[0154] When used in the treatments described herein, a therapeutically effective amount of an enantiomeric steroid modulator can be employed in pure form or, where such forms exist, in pharmaceutically acceptable salt form and with or without a pharmaceutically acceptable excipient. For example, the compounds of the present disclosure can be administered, at a reasonable benefit / risk ratio applicable to any medical treatment, in a sufficient amount to a pregnancy complication.

[0155] The amount of a composition described herein that can be combined with a pharmaceutically acceptable carrier to produce a single dosage form will vary depending upon the subject or host treated and the particular mode of administration. It will be appreciated by those skilled in the art that the unit content of agent contained in an individual dose of each dosage form need not in itself constitute a therapeutically effective amount, as the necessary therapeutically effective amount could be reached by administration of a number of individual doses.

[0156] Toxicity and therapeutic efficacy of compositions described herein can be determined by standard pharmaceutical procedures in cell cultures or experimental animals for determining the LDso (the dose lethal to 50% of the population) and the EDso, (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index that can be expressed as the ratio LD50 / ED50, where larger therapeutic indices are generally understood in the art to be optimal.

[0157] The specific therapeutically effective dose level for any particular subject will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the subject; the time of administration; the route of administration; the rate of excretion of the composition employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts (see e.g., Koda-Kimble et al. (2004) Applied Therapeutics: The Clinical Use of Drugs, Lippincott Williams & Wilkins, ISBN 0781748453; Winter (2003) Basic Clinical Pharmacokinetics, 4thed., Lippincott Williams & Wilkins, ISBN 0781741475; Sharqel (2004) Applied Biopharmaceutics & Pharmacokinetics, McGraw-Hill / Appleton & Lange, ISBN 0071375503). For example, it is well within the skill of the art to start doses of the composition at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. If desired, the effective daily dose may be divided into multiple doses for purposes of administration. Consequently, single-dose compositions may contain such amounts or submultiples thereof to make up the daily dose. It will be understood, however, that the total daily usage of the compounds and compositions of the present disclosure will be decided by an attending physician within the scope of sound medical judgment.

[0158] Again, each of the states, diseases, disorders, and conditions, described herein, as well as others, can benefit from compositions and methods described herein. Generally, treating a state, disease, disorder, or condition includes preventing, reversing, or delaying the appearance of clinical symptoms in a mammal that may be afflicted with or predisposed to the state, disease, disorder, or condition but does not yet experience or display clinical or subclinical symptoms thereof. Treating can also include inhibiting the state, disease, disorder, or condition, e.g., arresting or reducing the development of the disease or at least one clinical or subclinical symptom thereof. Furthermore, treating can include relieving the disease, e.g., causing regression of the state, disease, disorder, or condition or at least one of its clinical or subclinical symptoms. A benefit to a subject to be treated can be either statistically significant or at least perceptible to the subject or to a physician.

[0159] Administration of an enantiomeric steroid modulator can occur as a single event or over a time course of treatment. For example, an enantiomeric steroid modulator can be administered daily, weekly, bi-weekly, or monthly. For treatment of acute conditions, the time course of treatment will usually be at least several days. Certain conditions could extend treatment from several days to several weeks. For example, treatment could extend over one week, two weeks, or three weeks. For more chronic conditions, treatment could extend from several weeks to several months or even a year or more.

[0160] Treatment in accord with the methods described herein can be performed prior to, concurrent with, or after conventional treatment modalities for a pregnancy complication.

[0161] An enantiomeric steroid modulator can be administered simultaneously or sequentially with another agent, such as an antibiotic, an anti-inflammatory, or another agent. For example, an enantiomeric steroid modulator can be administered simultaneously with another agent, such as an antibiotic or an antiinflammatory. Simultaneous administration can occur through the administration of separate compositions, each containing one or more of an enantiomeric steroid modulator, an antibiotic, an anti-inflammatory, or another agent. Simultaneous administration can occur through the administration of one composition containing two or more of an enantiomeric steroid modulator, an antibiotic, an antiinflammatory, or another agent. An enantiomeric steroid modulator can be administered sequentially with an antibiotic, an anti-inflammatory, or another agent. For example, an enantiomeric steroid modulator can be administered before or after administration of an antibiotic, an anti-inflammatory, or another agent.

[0162] All publications, patents, patent applications, and other references cited in this application are incorporated herein by reference in their entirety for all purposes to the same extent as if each individual publication, patent, patent application, or other reference was specifically and individually indicated to be incorporated by reference in its entirety for all purposes. Citation of a reference herein shall not be construed as an admission that such is prior art to the present disclosure.

[0163] Having described the present disclosure in detail, it will be apparent that modifications, variations, and equivalent embodiments are possible without departing from the scope of the present disclosure defined in the appended claims. Furthermore, it should be appreciated that all examples in the present disclosure are provided as non-limiting examples.

[0164] EXAMPLES

[0165] The following non-limiting examples are provided to further illustrate the present disclosure. It should be appreciated by those of skill in the art that the techniques disclosed in the examples that follow represent approaches the inventors have found function well in the practice of the present disclosure, and thus can be considered to constitute examples of modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments that are disclosed and still obtain a like or similar result without departing from the spirit and scope of the present disclosure.

[0166] EXAMPLE 1 - RPE EVALUATION

[0167] The objective was to repurpose a former FDA-approved drug for preterm labor prevention known as Makena™ and its enantiomer- synthetic progestins that we have recently identified as a potent regulator of Kir7.111, and to explore whether these compounds can enhance the vital functions of RPE. The 17- hydroxy prog esterone caproate (17-OHPC; aka Makena™), not only specifically and potently activated Kir7.1 (Fig. 2C), but also showed a much stronger membrane retention, as demonstrated by a significantly longer washout time (Fig. 2C). Interestingly, the enantiomer of 17-OHPC (ent-17-OHPC or YX-49) has shown even better properties, ent-17-OHPC was able to activate human Kir7.1 with ECso of 520 nM and showed retention time greatly exceeding that of 17-OHPC (Figs. 2A-E). While 17-OHPC has been FDA-approved for a non-AMD use and its safety has been thoroughly evaluated, its enantiomer, YX-49, needs to be further evaluated on its Kir7.1 selectivity, cell toxicity and safety. Specifically, YX-49 will be introduced to HEK293 and hRPE-Kir7.1 cell culture to test compound toxicity, as well as to evaluate compound impact on RPE phagocytosis and transepithelial resistance. To carry in vitro phagocytosis assays in RPE cells, the GFP-labeled POS will be introduced and incubated with hRPE cells. The resulted fluorescence from engulfed POS will be analyzed. It is anticipated that a stronger Kir7.1 regulator added to the RPE cells during incubation will result in a greater uptake of POS by RPE.

[0168] EXAMPLE 2 - IN VIVO EFFICACY EVALUATION

[0169] To perform in vivo experiments to evaluate efficacy of the promising leads, including 17-OHPC and YX-49 using rodent animal model, the effects of the top leads on murine RPE recovery will be evaluated. In short, compounds will be administered via intravitreal injections to mice with a previously damaged RPE. The latter will be achieved by a classical method of intraperitoneal injection of sodium iodate (NalOs)25- a standard technique to evaluate novel therapeutic modalities for the treatment of retinal degenerations caused by primary failure of the RPE. The control group will be injected with either a vehicle, or ciliary neurotrophic factor (used as a positive control for neuroprotection). RPE recovery and global retinal cell function will be assessed with scotopic electroretinography three days post-NalOs administration. Additionally, retinal histology will be performed to assess RPE recovery and retinal morphology.

[0170] EXAMPLE 3 - SYNTHESIS OFXJ-49 (ENT-MAKENA) ent-Androstenedione (1).

[0171] To a solution of ent-testosterone26(250 mg, 0.87 mmol) in CH2CI2 (10 mL) was added Dess-Martin periodinane (550 mg, 1 .3 mmol) at 23 °C. After 1 .5 h, saturated aqueous NaHCOs was added and the product was extracted into CH2CI2 (20 mL x 3). The combined extracts were dried over anhydrous Na2SC>4 and filtered. The solvent was removed and the residue was purified by flash column chromatography (silica gel eluted with 20% EtOAc in hexanes) to give ent- androstenedione (1 , 246 mg, 99%):1H NMR (400 MHz, CDCh) 5 5.70 (s, 1 H), 2.44-0.88 (m, 19H), 1.17 (s, 3H), 0.87 (s, 3H);13C NMR (100 MHz, CDCh) 5 220.1 , 199.1 , 170.2, 123.9, 53.6, 50.7, 47.3, 38.5, 35.6, 35.5, 35.0, 33.8, 32.4, 31.1 , 30.6, 21.6, 20.1 , 17.2, 13.5. ent-[(17a)-17-Hydroxy-3-oxoandrost-4-ene-17-carbonitrile] (2).

[0172] Acetic acid (0.1 mL, 1.4 mmol) was added over a period of 20 min at 23 °C to ent- androstenedione (246 mg, 0.86 mmol) and KCN (227 mg, 3.5 mmol) in MeOH (5 mL). After 16 h, acetic acid (0.15 mL, 2.1 mmol) was added and the reaction was stirred for 15 min. After dilution with water and saturated aqueous NaHCOs, the product was extracted into EtOAc (30 mL x 2). The combined extracts were washed with brine (50 mL), water (50 mL), dried over anhydrous Na2SC>4 and filtered. The solvent was removed to give enf-steroid 2 (270 mg , 100%):1H NMR (400 MHz, CDCh) 8 5.75 (s, 1 H), 3.50-3.48 (m, 1 H), 2.48-0.86 (m, 19H), 1.20 (s, 3H), 0.98 (s, 3H);13C NMR (100 MHz, CDCh) 8 200.1 , 171.3, 123.9, 120.9, 77.6, 53.0, 49.0, 47.6, 38.5, 38.1 , 35.9, 35.6, 33.8, 32.7, 31.9, 29.3, 23.8, 20.3, 17.3, 16.2. ent-[[(17a)-3,3-[1 ,2-Ethanediylbis(oxy)]-17-hydroxyandrost-5-ene-17- carbonitrile] (3).

[0173] To a solution of enf-steroid 2 (270 mg, 0.86 mmol) in benzene (80 mL) was added ethyl glycol (2 mL, 35.8 mmol) and p-toluenesulfonic acid (20 mg) at 23 °C. The reaction was refluxed in a flask equipped with a Dean-Stark apparatus. After 16 h, the reaction was cooled to 23 °C and saturated aqueous NaHCOs was added. The product was extracted into EtOAc (100 mL). The EtOAc was washed with brine (100 mL x 5), dried over anhydrous Na2SO4 and filtered. The solvent was removed and the residue was purified by flash column chromatography (silica gel eluted with 10-20% EtOAc in hexanes) to give enf-steroid 3 (220 mg, 72%):1HNMR (400 MHz, CDCh) 8 5.32-5.31 (s, 1 H), 4.04-3.95 (m, 4H), 3.38 (s, 1 H), 2.61-2.57 (m, 1 H), 2.44-2.37 (m, 1 H), 2.13-0.88 (m, 17H), 1.04 (s, 3H), 0.95 (s, 3H);13C NMR (100 MHz, CDCI3) 8 139.9, 121.9, 121.4, 109.7, 77.6, 64.3, 64.3, 49.0, 48.9, 48.7, 41.9, 38.4, 36.4, 35.9, 32.2, 31.7, 30.8, 29.5, 24.1 , 20.4, 19.0, 16.1. ent-[(17a)-3,3-[1,2-ethanediylbis(oxy)]-17-(1-ethoxyethoxy)-androst-5-ene-17- carbonitrile] (4).

[0174] To a solution of ent-steroid 3 (220 mg, 0.62 mmol) in CH2CI2 (5 mL) ethyl vinyl ether (1 mL, 10.5 mmol) and pyridine hydrochloride (10 mg, 0.09 mmol) were added at 23 °C. The reaction was heated at 55 °C for 16 h. After cooling to 23 °C, the solvent was removed and the residue was purified by flash column chromatography (silica gel eluted with 10% -20% EtOAc in hexanes) to give ent- steroid 4 (230 mg, 85%):1H NMR (400 MHz, CDCh) 85.34-5.33 (m, 1 H), 5.09- 5.05 (m, 1 H), 4.00-3.90 (m, 4H), 3.59-3.55 (m, 1 H), 3.49-3.45 (m, 1 H), 2.58-2.50 (m, 2H), 2.22-0.88 (m, 23 H), 1.04 (s, 3H), 0.96 (s, 3H);13C NMR (100 MHz, CDCb) 5 140.2, 121.5, 119.3, 109.3, 98.3, 83.3, 64.4, 64.2, 59.5, 50.0, 49.2, 49.1 , 41.7, 36.5, 36.3, 34.4, 32.4, 31.7, 31.0, 29.4, 24.3, 20.4, 20.4, 18.9, 16.2, 15.3. ent-(17a-Hydroxyprogesterone) (5)

[0175] A solution of enf-steroid 4 (230 mg, 0.53 mmol) in EbO (10 mL) was cooled to 0 °C and MeLi (3 mL, 1 .6 M in Et20, 4.8 mmol) was added. The reaction was heated at 40 °C for 5 h. The reaction was cooled to 0 °C and Et?O (20 mL) was added followed by the addition of 3N HCI (5 mL, 15 mmol). Stirring was continued for 16 h and the product was extracted into EtOAc (100 mL x 2). The combined extracts were washed with saturated aqueous NaHCOs (50 mL), water (50 mL), brine (50 mL), dried over Na2SC>4 and filtered. The solvent was removed and the residue was purified by flash column chromatography (silica gel eluted with 10-20% EtOAc in hexanes) to give enf-[17a-hydroxyprogesterone] (5, 110 mg, 62%):1H NMR (400 MHz, CDC ) 8 5.67 (s, 1 H), 3.24 (s, 1 H), 2.64-2.61 (m, 1 H), 2.21 (s, 3H), 1.14 (s, 3H), 0.68 (s, 3H), 2.36-0.63 (m, 18H);13C NMR (100 MHz, CDCb) 8211 .4, 199.5, 171.3, 123.7, 89.7, 53.2, 49.9, 47.7, 38.4, 35.5, 35.3, 33.7, 33.2, 32.7, 31.9, 30.0, 27.5, 23.7, 20.4, 17.2, 15.1. ent-[17a-Hydroxy progesterone caproate] (6, YX-49, ent-Makena). enf-[17a-Hydroxyprogesterone] (5,110 mg, 0.33 mmol) and hexanoic anhydride (140 mg, 0.7mmol), p-toluenesulfonic acid (10 mg) and dry benzene (5 mL) were heated at 80 °C until a clear solution was obtained. The solution was allowed to stand at room temperature for 18 h, poured into ice and water, and stirred to effect hydrolysis of the excess anhydride. The product was extracted into Et2<3 and the combined extracts were washed with NaOH solution (50 mL, 1 M), water (50 mL), dried over anhydrous Na2SO4 and filtered. The solvent was removed, and the residue was purified by flash column chromatography (silica gel eluted with 20% EtOAc in hexanes) to give enf-[17a-Hydroxyprogesterone caproate] (6 ,85 mg, 60%):1H NMR (400 MHz, CDCb) 8 5.74 (s, 1 H), 2.98-2.90 (m, 1 H), 2.50-0.87 (m, 29H), 2.03 (s, 3H), 1.19 (s, 3H), 0.67 (s, 3H);13C NMR (100 MHz, CDCb) 8 204.0, 199.3, 173.3, 170.6, 123.9, 96.4, 53.1 , 51.2, 46.8, 38.5, 35.7, 35.6, 34.4, 33.9, 32.7, 31.9, 31.2, 31.0, 30.3, 26.3, 24.5, 23.8, 22.2, 20.6, 17.3, 14.3, 13.9. Optical rotation: aD23-63 (CHCh, c = 0.20). Reported literature value for natural 17a- Hydroxyprogesterone caproate: aD25+ 61 (CHCh, c = 1 ).27

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Claims

ClaimsWhat is claimed is:

1. A compound of Formula Iwherein:Ri is independently selected from the group consisting of hydrogen, methyl, and ethyl; andR2 is independently selected from the group consisting of straight-chained or branched alkyl, straight-chained or branched alkenyl, and straight-chained or branched alkynyl, or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the alkyl group has from 1 to 20 carbon atoms, from 2 to 20 carbon atoms, from 1 to 10 carbon atoms, from 2 to 10 carbon atoms, from 1 to 8 carbon atoms, from 2 to 8 carbon atoms, from 1 to 6 carbon atoms, from 2 to 6 carbon atoms, from 1 to 4 carbon atoms, from 2 to 4 carbon atoms, from 1 to 3 carbon atoms, or 2 or 3 carbon atoms.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the alkenyl group has from 2 to 10 carbon atoms, from 2 to 8 carbon atoms, from 2 to 6 carbon atoms, from 2 to 4 carbon atoms, from 3 to 10 carbon atoms, from 3 to 8 carbon atoms, from 3 to 6 carbon atoms, or 3 or 4 carbon atoms.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the alkynyl group has from 2 to 10 carbon atoms, from 2 to 8 carbon atoms, from 2 to 6 carbon atoms, or from 2 to 4 carbon atoms.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is6. A pharmaceutical composition comprising a compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

7. The pharmaceutical composition of claim 6, wherein the pharmaceutically acceptable carrier is a saline solution or an eye drop formulation.

8. The pharmaceutical composition of claim 6, further comprising (2- hydroxypropyl)-p-cyclodextrin.

9. A method of preventing or treating age-related macular degeneration (AMD) comprising administering a therapeutically effective amount of a compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof.

10. The method of claim 9, wherein the age-related macular degeneration (AMD) is dry AMD.11 . The method of claim 9, wherein administering a therapeutically effective amount of the composition comprises administering the composition by intravitreal injection or intracameral injection or via eye drops.

12. The method of claim 9, wherein the compound, or pharmaceutically acceptable salt thereof is administered at a concentration of from about 10 nM to about 100 pM.

13. The method of claim 9, wherein the compound is14. A method of preventing or treating age-related macular degeneration (AMD) comprising administering a therapeutically effective amount of a composition comprising enf-progesterone, or a pharmaceutically acceptable salt thereof.

15. The method of claim 14, wherein the composition further comprises a saline solution.

16. The method of claim 14, wherein the composition further comprises (2-hydroxypropyl)-p-cyclodextrin.

17. The method of claim 14, wherein the age-related macular degeneration (AMD) is dry AMD.

18. The method of claim 14, wherein administering a therapeutically effective amount of the composition comprises administering the composition by intravitreal injection or intracameral injection or via eye drops.

19. The method of claim 14, wherein the composition comprises ent- progesterone, or a pharmaceutically acceptable salt thereof, in a concentration of from about 10 nM to about 100 pM.

20. A method of preparing enf-[17a-hydroxyprogesterone caproate] (6) comprising the steps of:1 ) converting ent-testosterone to ent-androstenedione (1 );2) converting enAandrostenedione (1 ) to enf-[(17a)- 17-hydroxy-3- oxoandrost-4-ene-17-carbo nitrile] (2);3) converting ent-[(17a)-17-hydroxy-3-oxoandrost-4-ene-17-carbonitrile] (2) to ent-[17a-3,3-(1 ,2-ethanediylbis(oxy))-17-hydroxyandrost-5-ene-17- carbonitrile] (3);4) converting ent-[17a-3,3-(1 ,2-ethanediylbis(oxy))-17-hydroxyandrost- 5-ene-17-carbonitrile] (3) to ent-[(17a)-3,3-(1 ,2-ethanediylbis(oxy))-17-(1- ethoxyethoxy)-androst-5-ene-17-carbonitrile] (4);5) converting ent-[(17a)-3,3-(1 ,2-ethanediylbis(oxy))-17-(1- ethoxyethoxy)-androst-5-ene-17-carbonitrile] (4) to ent-[17a-hydroxyprogesterone] (5);6) converting ent-[17a-hydroxyprogesterone] (5) to enf-[17a- hydroxy prog esterone caproate] (6).21 . A method of preventing or treating a pregnancy complication comprising administering a therapeutically effective amount of a compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof via intramuscular, or intravenous, or intraperitoneal injections or delivered topically.

22. The method of claim 21 , wherein the pregnancy complication is selected from preterm labor and preeclampsia.

23. The method of claim 21 , wherein administering a therapeutically effective amount of the composition comprises administering the composition by intramuscular, or intravenous, or intraperitoneal injections or delivered topically.

24. The method of claim 21 , wherein the compound, or pharmaceutically acceptable salt thereof is administered at a concentration of from about 10 nM to about 100 pM.

25. The method of claim 21 , wherein the compound is26. A method of preventing or treating a pregnancy complication comprising administering a therapeutically effective amount of a composition comprising enf-progesterone, or a pharmaceutically acceptable salt thereof.

27. The method of claim 26, wherein the composition further comprises a saline solution, or ethanol, or DMSO, or mineral oil based solutions.

28. The method of claim 26, wherein the composition further comprises (2-hydroxypropyl)-p-cyclodextrin.

29. The method of claim 26, wherein the pregnancy complication is selected from preterm labor and preeclampsia.

30. The method of claim 26, wherein administering a therapeutically effective amount of the composition comprises administering the composition by intramuscular, or intravenous, or intraperitoneal injections or delivered topically.31 . The method of claim 26, wherein the composition comprises ent- progesterone, or a pharmaceutically acceptable salt thereof, in a concentration of from about 10 nM to about 100 pM.

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