55 results about "Subtype selectivity" patented technology

Disclosed herein are compounds and methods for treating chronic neuropathic pain. It has been discovered that compounds that selectively interact with a muscarinic receptor subtype are effective in treating neuropathic pain. Specifically, compounds that selectively interact with the M1 muscarinic receptor subtype may be used.

Novel peptides which are conformationally constrained backbone cyclized somatostatin analogs, having somatostatin receptor subtype selectivity are disclosed. These patterns or receptor subtype selectivity provide compounds having improved therapeutic utility. Methods for synthesizing the somatostatin analogs and for screening of the somatostatin analogs are also disclosed. Furthermore, pharmaceutical compositions comprising somatostatin analogs, and methods of using such compositions are disclosed.

This invention relates to the use of EP2 receptor subtype selective prostaglandin E2 agonists to augment bone mass including the prevention and treatment of skeletal disorders in mammals, including humans.

The invention discloses E-configuration benzamide compounds, and a pharmaceutical preparation application thereof. The structure of the E-configuration benzamide compounds is disclosed as Formula (I); the chemical name is N-(2-amino-4-fluorophenyl)-4-[N-[(E)-3-(3-pyridyl)acryloyl]aminomethyl]benzamide; and in the structural formula, the configuration of the 3-pyridylacryloyl group is E. The E-configuration benzamide compounds disclosed as Formula (I) have subtype selective histone deacetylase inhibition activity, and are mainly used for inhibiting HDAC1, HDAC2 and HDAC3 in Class I HDAC and HDAC10 in Class IIb HDAC. The E-configuration benzamide compounds disclosed as Formula (I) can be used for treating diseases related to histone deacetylase activity abnormity, such as cancers, including lymphomata, entity tumor, blood system tumors and the like.

A compound having selective modulating activity at the alpha 2B and / or alpha 2C adrenergic receptor subtypes is represented by the general Formula 1:whereinn=1-4;X is C or N;R1-R6 can be the same or different and are independently selected from the group consisting of H, C1-6 alkyl, OCH3, OH, F, Cl, Br, CH2OH, CH2N(R7)2, C(O)R8, CH2CN, CF3;wherein R7 is H or C1-6 alkyl; andR8 is C1-6 alkyl or aryl.The compounds of Formula 1 can be incorporated in pharmaceutical compositions and used in methods of treatment of alpha 2 receptor mediated diseases and conditions.

The invention relates to a hydantoin hydroxamic acid type selective inhibitor for a histone deacetylase 6 subtype and a preparation method and applications thereof. The selective inhibitor has a structure represented by the formula (I). The selective inhibitor has good activities on inhibiting the activity of histone deacetylase and preventing the proliferation of tumor cells and can be used to prepare drugs for treating or preventing diseases of mammals caused by abnormal expression of histone deacetylase. The invention further relates to a pharmaceutical application of a composition that contains the inhibitor represented by the formula (I).

Disclosed are chemical entities of Formula (I):wherein R1 and Z are defined herein, as NR2B subtype selective receptor antagonists. Also disclosed are pharmaceutical compositions comprising a chemical entity of Formula (I), and methods of treating various diseases and disorders associated with NR2B antagonism, e.g., diseases and disorders of the CNS, such as depression, by administering a chemical entity of Formula (I).

The invention provides a compound as shown in a formula I which is described in the specification and a pharmaceutically acceptable salt thereof and specifically relates to a novel 4-arylaminoquinazoline hydroxamic acid compound with histone deacetylase inhibitory activity, a preparation method for the compound, a pharmaceutical composition including the compound, and application of the compound and the pharmaceutical composition in preparation of histone deacetylase inhibitor drugs. The objective of the invention is to acquire a series of selective histone deacetylase inhibitors with subtype selectivity and good pharmacokinetic characteristics through optimization of enzyme surface recognition regions and joining regions of 4-arylaminoquinazoline via drug design and synthesis means so as to improve antineoplastic activity and reduce influence on normal tissue or cells.

The invention relates to a three-dimensional crystal structure model of alpha1-AR subtype protein and an establishment method thereof. The establishment method comprises the following steps of searching a protein crystal database with an amino acid sequence of the alpha1-AR subtype protein as a probe and obtaining a homologous template beta2-AR with the highest similarity through comparison with the amino acid sequence; utilizing a Prime module of (formula) to carry out homology modeling on the alpha1-AR subtype protein; and adopting an Macromodel module to optimize protein obtained by homology modeling and obtaining the three-dimensional crystal structure model of the alpha1-AR subtype protein through model evaluation. The invention provides model conformations of three alpha1-AR subtype proteins, namely alpha1A-AR, alpha1B-AR and alpha1D-AR and provides the basis for accurately researching structure-function relationship between a target spot and an antagonist; a possible binding packet is modelled, a key residue is found, and the theoretical basis is provided for explaining the selectivity of an alpha1-AR subtype selective antagonist.

The present invention relates to analgesic applications of a polypeptide toxin mu-EPTX-Na1a (short for Na1a) from Naja atra. According to the present invention, the Na1a provides a strong inhibition effect for the voltage-gated sodium channel subtype Nav1.8, wherein the half-maximal inhibition concentration is 167 nM; the subtype selectivity shows that the Na1a is highly specific; the pharmacodynamics activity experiment results show that the Na1a provides stronger analgesic activities in acetic acid writhing pain models, formalin pain models and complete Freund's adjuvant pain models compared to morphine, and provides similar or slightly excellent analgesic activities in hot plate pain models and sciatic nerve ligation models compared to morphine; the evaluation results of the side effects of the Na1a show that the weak side effects are provided in the movement function, the cardiotoxicity, the hemolytic activity and the cytotoxic activity; and the Na1a is the analgesic polypeptide having the application value.

The invention particularly discloses a high-flux screening cell model of an alpha1-AR subtype selective antagonist, and a construction method and application thereof. The construction method comprises the following steps: co-transfecting eukaryotic expression plasmids, reporter genes and internal reference plasmids of three alpha1-AR subtypes (alpha1A, alpha1B and alpha1D) to a host cell, thus establishing a transient transfection cell model; successively adding an antagonist to be screened and an agonist into the cell model, and co-culturing for a period of time until cells crack; and performing luciferase activity determination on the cracked products, and determining relative expression quantities of the reporter genes and the internal references, thereby evaluating the inhibition activity of the medicament on the three alpha1-AR subtypes (alpha1A, alpha1B and alpha1D). The method passes model stability / volatility inspection and model verification. The cell model can be used for high-flux screening of an alpha1-AR subtype selective antagonist, and can be further used for screening of potential medicaments for treating benign prostatic hyperplasia.

The invention provides well-defined heterocyclic compounds that are useful as subtype selective alpha 2 adrenergic agonists. As such, the compounds described herein are useful in treating a wide variety of disorders associated with selective subtype modulation of alpha 2 adrenergic receptors.

Methods of use of pharmaceutical compositions and novel peptides which are conformationally constrained backbone cyclized somatostatin analogs, having somatostatin receptor subtype selectivity, are disclosed. These patterns or receptor subtype selectivity provide compounds having improved therapeutic utility. Methods for synthesizing the somatostatin analogs and for screening of the somatostatin analogs are also disclosed. Furthermore, pharmaceutical compositions comprising somatostatin analogs are disclosed.

A compound having selective modulating activity at the alpha 2B and or alpha 2C adrenergic receptor subtypes is represented by the general Formula (1): wherein R1-R6 is independently selected from the group consisting of H, C1-6 alkyl, halogen, CH2OH, CH2N(R7)2) CH2CN, C(O)R8, CF3, and aryl; wherein R7 is H or C1-6 alkyl; and R8 is H, C1-6 alkyl or aryl. The compounds of Formula (1) can be incorporated in pharmaceutical compositions and used in methods of treatment of alpha 2 receptor mediated diseases and conditions.

The invention belongs to the technical field of medical chemistry, and particularly relates to a 1-aminobenzo [4, 5] imidazo [1, 2-a] pyrazine-3-formamide compound and preparation and application thereof.The structure of the compound is shown in the formula (I), and the compound is novel in structure, is an adenosine receptor inhibitor, and can be used for preparing a novel compound. The compound has good inhibitory activity on adenosine A2A receptors and good subtype selectivity, can be used as a targeted adenosine A2A receptor inhibitor for immunotherapy, and achieves the effect of treating tumors by inhibiting the activity of the adenosine A2A receptors and releasing the removal function of an immune system on tumor cells. Meanwhile, the preparation method of the compound is simple, the cheap and easily available compound is used as the raw material, the reaction condition is mild, the total yield and the purity are high, the production of dozens of grams can be realized, and the research of later clinical candidate adenosine A2A receptor inhibitors is supported.

Disclosed are an E-configuration benzamide compound and pharmaceutical formulation and application thereof. The E-configuration benzamide compound has a structure represented by formula (I), with the chemical name of N-(2-amino-4-fluorophenyl)-4-[N-[(E)-3-(3-pyridine) acryl] aminomethyl] benzamide, and 3-pyridine acryl in the structural formula having E-configuration. The E-configuration benzamide compound represented by formula (I) has subtype selective histone deacetylated enzyme inhibitory activity, mainly inhibiting HDAC1, HDAC2, HDAC3 in type I HADC and HDAC10 in type IIb HDAC. The E-configuration benzamide compound represented by formula (I) can be used to treat diseases related to abnormal activity of the histone deacetylated enzyme, such as cancer, including lymphoma, solid tumor and blood system tumor and the like.

The invention belongs to the field of biologic medicines, and particularly relates to an application of autocrine VEGF-B to T cell metabolism and functions as well as tumor immunity treatment. For thefirst time, the invention discloses that blood vessel endothelium growth factors B(VEGF-B) are metabolism adjusting and controlling factors selectively secreted by different subtypes of activated T cells. Through antibodies, or peptide activated T cells, and / or excitants which can promote biologic synthesis of mitochondria, or reagents for adjusting and controlling ROS / AP-1 signals pertinent to the mitochondria, the activated T cells can be induced by a ROS / AP-1 signal channel to secrete VEGF-B, so that fatty acid ingestion, apoptosis resistance, tumor resistance activity and the like of theT cells can be promoted. The metabolism of T lymphocytes is programmed through tumor microenvironment, and the autocrine VEGF-B has great application prospects in tumor immunity treatment.

Compounds, pharmaceutical compositions including the compounds, and methods of preparation and use thereof are disclosed. The compounds are amide, ketone, and ester compounds prepared from certain azabicycloalkane carboxylic acids. The resulting compounds exhibit selectivity for, and bind with high affinity to, neuronal nicotinic receptors of the α4β2 subtype in the central nervous system (CNS). The compounds and compositions can be used to treat and / or prevent a wide variety of conditions or disorders, such as those disorders characterized by dysfunction of nicotinic cholinergic neurotransmission, including disorders involving neuromodulation of neurotransmitter release, such as dopamine release. CNS disorders, which are characterized by an alteration in normal neurotransmitter release, are another example of disorders that can be treated and / or prevented. The compounds can: (i) alter the number of nicotinic cholinergic receptors of the brain of the patient, (ii) exhibit neuroprotective effects, and (iii) when employed in effective amounts, not result in appreciable adverse side effects (e.g. side effects such as significant increases in blood pressure and heart rate, significant negative effects upon the gastrointestinal tract, and significant effects upon skeletal muscle).

A compound represented by Formula I or pharmaceutically acceptable salt thereof. The present invention relates to a 4-arylamino quinazoline hydroxamic acid compound having a histone deacetylase inhibitory activity, preparation method of the compound, pharmaceutical composition comprising the compound, and use of the compound and the pharmaceutical composition in the preparation of a histone deacetylase inhibitor medicine. The present invention aims at acquiring, via a medicine design and a synthetic technology, a series of selective histone deacetylase inhibitors having good hypotype selectivity and favorable pharmacokinetic characteristics based on optimization of an enzyme surface recognition region and connection region of 4-arylamino quinazoline, thus reducing an effect on normal tissues or cells while improving an antineoplastic activity of the normal tissues or cells.

The invention relates to a model building method and application of a G protein coupled receptor (GPCR) on a new platform, in particular to model building and application of two subtypes, namely an Atype (ETA receptor) and a B type (ETB receptor), of an endothelin receptor on different cell lines by using an unmarked cell dynamic mass reset technology. The ETA receptor model is constructed on anSH-SY5Y cell line and a PC3 cell line for endogenously expressing ETA receptors respectively, and the ETB receptor model is constructed on a U251 cell line for endogenously expressing ETB receptors. The method has the characteristics of being close to the real environment in vivo, unmarked, real-time in monitoring, high in flux and simple to operate, can screen the ETA receptor and ETB receptor ligands (including agonists and antagonists) with subtype selectivity, and can compare the results of the same compound on the two receptors in the same ratio.

The present invention provides compounds which are subtype selective antagonists of the alpha 2B adrenergic receptor and have no or weak antagonist activity at the other alpha adrenergic receptors. These compounds are useful as tool compounds and, in particular, as tool compounds for developing compounds useful in treating diseases that include but are not limited to chronic pain, visceral pain, corneal pain, neuropathic pain, glaucoma, ischemic neuropathies and other neurodegenerative diseases and conditions. These compounds are also useful as compounds for treating myocardial infarction and preventing acute coronary events. The compounds of this invention are 3-amino-1-thioxo or oxo-1,2,5,6,7,8-hexahydro-2,7-naphthyridine-4-carbonitriles or substituted derivatives thereof.

The invention belongs to the fields of gene technology and pharmacy, and discloses a highly expressed human source (Homosapiens) PARP-2 catalytic domain mutant protein and an application thereof. The method comprises the following steps: carrying out sequence alignment on PARP-2 catalytic structural domains of a human source and a mouse source, and designing a mutant. According to the present invention, the Tm value of the mutant catPARP-2SE (the codon of the nucleotide sequence is optimized, and the 349TELQSP354 is mutated to 349SERQGL354) is determined by using a differential scanning fluorescence method (Diffraction ScanningFluorometry), and the Tm value of the mutant catPARP-2SE is increased by about 1.11 DEG C, wherein the codon of the nucleotide sequence is optimized, and the 349TELQSP354 is mutated to 349SERQGL354; compared with a wild type, the mutant has the advantages that the thermal stability is enhanced, the expression quantity in an Escherichiacoli system is improved by more than four times, and the enzyme level activity evaluation and protein crystallization experiment of the PARP inhibitor are favorably carried out. The protein crystallization temperature is increased to 25 DEG C from 4 DEG C, so that the difficulty of obtaining a protein-ligand compound structure is greatly reduced, and the PARP-2 inhibitor design based on a protein structure is favorably developed. The catPARP-2SE has two characteristics of high expression quantity and crystallization in an environment close to room temperature, and can be applied to discovery of PARP-2 selective / non-selective inhibitors or PARP family other subtype selective inhibitors.

The present invention relates to 1,2,4,5-tetrasubstituted imidazole derivatives as selective cannabinoid CB1 receptor modulators, in particular CB1 receptor antagonists or inverse agonists having a high CB1 / CB2 receptor subtype selectivity, to methods for the preparation of these compounds and to novel intermediates useful for the synthesis of said imidazole derivatives. The invention also relates to the use of a compound disclosed herein for the manufacture of a medicament giving a beneficial effect. A beneficial effect is disclosed herein or apparent to a person skilled in the art from the specification and general knowledge in the art. The invention also relates to the use of a compound of the invention for the manufacture of a medicament for treating or preventing a disease or condition. More particularly, the invention relates to a new use for the treatment of a disease or condition disclosed herein or apparent to a person skilled in the art from the specification and general knowledge in the art. In embodiments of the invention specific compounds disclosed herein are used for the manufacture of a medicament useful in the treatment of psychiatric and neurological disorders. The compounds have the general formula (I) wherein the symbols have the meanings given in the specification.

The invention provides well-defined heterocyclic compounds that are useful as subtype selective alpha 2 adrenergic agonists. As such, the compounds described herein are useful in treating a wide variety of disorders associated with selective subtype modulation of alpha 2 adrenergic receptors.

The invention provides a selective KCNQ channel opener and application of the selective KCNQ channel opener in pharmacy. According to the invention, a series of KCNQ channel openers with high selectivity are obtained by carrying out structural modification and activity and selectivity evaluation on a KCNQ2 agonist 124-A10 (CAS number: 1173735-00-6) obtained by screening. Compared with common KCNQ channel openers, such as retigabine, ICA27243 and the like, the subtype selectivity of the compounds is enhanced, so that some toxic and side effects generated in the application of pharmaceutical preparations due to poor selectivity can be effectively avoided. The invention also provides applications of the compounds in preparation of anti-epileptic drugs, anti-schizophrenia drugs, anti-depression drugs and drugs for treating cerebral arterial thrombosis diseases, and provides more effective choices for treatment of related diseases.

A method of treating, preventing, or ameliorating a pathological condition associated with a melatonin receptor in a mammal by using a pharmaceutical composition containing a compound of formula (I) as a ligand interacting with the melatonin receptor,R1, R2, R3, R4 and R7 are independently H, halo, alkyloxyl, alkyl or hydroxyl, provided that one of R1, R2, R3 and R7 is X—(CH2)n—R8; R5 is alkyl or arylalkyl; R6 is H or alkyl; X is a bond, O, S, SO, SO2, CO or NH; n=0-10; R8 is alkenyl, substituted or unsubstituted aryl, NR9R10, or OR9; R9 is H, substituted or unsubstituted arylmethyl, or alkenyl; and R10 is H or alkyl.

The present invention belongs to the field of radiopharmaceutical chemistry and clinical nuclear medicine, and specifically relates to a preparation method and application of imidazopyridone compounds that bind to sigma-2 (σ2) receptors. The general structural formula of the compound is shown in formula (I), which has nanomolar affinity, high subtype selectivity and specificity for σ2 receptors / TMEM97. When the R group in the compound of formula (I) is 18 F, after 18 F-OTs-substituted labeled precursors undergo nucleophilic substitution to prepare corresponding tracers, which have high radiochemical yield and radiochemical purity, excellent biological properties, and can be used for PET imaging of tumor proliferation and atherosclerotic plaques, with broad clinical application prospects. #imgabs0#

The invention discloses an HDAC6 inhibitor, a medicinal composition and application, relates to the technical field of medicines, and solves the technical problems that the existing HDAC6 is poor in selectivity and poor in brain permeability and metabolic stability. The HDAC6 inhibitor disclosed by the invention is selected from any one or more of compounds with structural formulas as shown in formulas 1-13, meanwhile, the invention provides a preparation method of the compounds with the formulas 1-13, and on the basis, the invention further provides a medicinal composition comprising the inhibitor and a pharmaceutically acceptable carrier or auxiliary material thereof. According to the HDAC6 inhibitor provided by the invention, the inhibition activity is effectively improved, the subtype selectivity, fat solubility and metabolic stability to molecules are improved, and the HDAC6 inhibitor has high brain penetration.