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Your search keyword '"Deng, Qiaolin"' showing total 7 results
Start Over Author "Deng, Qiaolin" Topic receptors, g-protein-coupled
7 results on '"Deng, Qiaolin"'

1. The discovery of potent antagonists of NPBWR1 (GPR7).

Author

Anthony Romero F, Hastings NB, Moningka R, Guo Z, Wang M, Di Salvo J, Lei Y, Trusca D, Deng Q, Tong V, Terebetski JL, Ball RG, and Ujjainwalla F

Subjects
Animals, Benzylamines chemical synthesis, Benzylamines chemistry, Crystallography, X-Ray, Dose-Response Relationship, Drug, Humans, Mice, Models, Molecular, Molecular Structure, Piperazine, Piperazines chemical synthesis, Piperazines chemistry, Stereoisomerism, Structure-Activity Relationship, Benzylamines pharmacology, Piperazines pharmacology, Receptors, G-Protein-Coupled antagonists & inhibitors, Receptors, Neuropeptide antagonists & inhibitors
Abstract

The synthesis and evaluation of small molecule antagonists of the G protein-coupled receptor NPBWR1 (GPR7) are reported for the first time. [4-(5-Chloropyridin-2-yl)piperazin-1-yl][(1S,2S,4R)-4-{[(1R)-1-(4-methoxyphenyl)ethyl]amino}-2-(thiophen-3-yl)cyclohexyl]methanone (1) emerged as a hit from a high-throughput screen. Examination of substituents that focused on replacing the 5-chloropyridine and 4-methoxybenzylamino groups of 1 led to the identification of compounds that exhibited subnanomolar potencies as low as 660pM (9k) in the functional assay and 200pM in the binding assay (9i)., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Published
2012
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2. Discovery of a biaryl cyclohexene carboxylic acid (MK-6892): a potent and selective high affinity niacin receptor full agonist with reduced flushing profiles in animals as a preclinical candidate.

Author

Shen HC, Ding FX, Raghavan S, Deng Q, Luell S, Forrest MJ, Carballo-Jane E, Wilsie LC, Krsmanovic ML, Taggart AK, Wu KK, Wu TJ, Cheng K, Ren N, Cai TQ, Chen Q, Wang J, Wolff MS, Tong X, Holt TG, Waters MG, Hammond ML, Tata JR, and Colletti SL

Subjects
Animals, Area Under Curve, Binding, Competitive, CHO Cells, Carboxylic Acids chemistry, Carboxylic Acids pharmacokinetics, Cricetinae, Cricetulus, Cyclohexanecarboxylic Acids chemistry, Cyclohexanecarboxylic Acids pharmacokinetics, Dogs, Drug Evaluation, Preclinical, Fatty Acids, Nonesterified blood, Humans, Metabolic Clearance Rate, Mice, Mice, Inbred C57BL, Mice, Knockout, Models, Chemical, Molecular Structure, Oxadiazoles chemistry, Oxadiazoles pharmacokinetics, Rats, Receptors, G-Protein-Coupled genetics, Receptors, G-Protein-Coupled metabolism, Receptors, Nicotinic genetics, Receptors, Nicotinic metabolism, Structure-Activity Relationship, Vasodilation drug effects, Carboxylic Acids pharmacology, Cyclohexanecarboxylic Acids pharmacology, Cyclohexenes chemistry, Drug Discovery, Oxadiazoles pharmacology, Receptors, G-Protein-Coupled agonists
Abstract

Biaryl cyclohexene carboxylic acids were discovered as full and potent niacin receptor (GPR109A) agonists. Compound 1e (MK-6892) displayed excellent receptor activity, good PK across species, remarkably clean off-target profiles, good ancillary pharmacology, and superior therapeutic window over niacin regarding the FFA reduction versus vasodilation in rats and dogs.

Published
2010
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3. Discovery of novel tricyclic full agonists for the G-protein-coupled niacin receptor 109A with minimized flushing in rats.

Author

Shen HC, Ding FX, Deng Q, Wilsie LC, Krsmanovic ML, Taggart AK, Carballo-Jane E, Ren N, Cai TQ, Wu TJ, Wu KK, Cheng K, Chen Q, Wolff MS, Tong X, Holt TG, Waters MG, Hammond ML, Tata JR, and Colletti SL

Subjects
Adipocytes drug effects, Adipocytes metabolism, Animals, CHO Cells, Cricetinae, Cricetulus, Cycloparaffins adverse effects, Cycloparaffins pharmacology, Ear blood supply, Heterocyclic Compounds, 3-Ring adverse effects, Heterocyclic Compounds, 3-Ring pharmacology, Humans, Hypolipidemic Agents adverse effects, Hypolipidemic Agents pharmacology, In Vitro Techniques, Lipolysis, Male, Mice, Radioligand Assay, Rats, Receptors, Nicotinic, Structure-Activity Relationship, Vasodilation drug effects, ortho-Aminobenzoates adverse effects, ortho-Aminobenzoates pharmacology, Cycloparaffins chemical synthesis, Flushing chemically induced, Heterocyclic Compounds, 3-Ring chemical synthesis, Hypolipidemic Agents chemical synthesis, Niacin metabolism, Receptors, G-Protein-Coupled agonists, ortho-Aminobenzoates chemical synthesis
Abstract

Tricyclic analogues were rationally designed as the high affinity niacin receptor G-protein-coupled receptor 109A (GPR109A) agonists by overlapping three lead structures. Various tricyclic anthranilide and cycloalkene carboxylic acid full agonists were discovered with excellent in vitro activity. Compound 2g displayed a good therapeutic index regarding free fatty acids (FFA) reduction and vasodilation effects in rats, with very weak cytochrome P450 2C8 (CYP2C8) and cytochrome P450 2C9 (CYP2C9) inhibition, and a good mouse pharmacokinetics (PK) profile.

Published
2009
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4. Molecular modeling aided design of nicotinic acid receptor GPR109A agonists.

Author

Deng Q, Frie JL, Marley DM, Beresis RT, Ren N, Cai TQ, Taggart AK, Cheng K, Carballo-Jane E, Wang J, Tong X, Waters MG, Tata JR, and Colletti SL

Subjects
Binding Sites, Combinatorial Chemistry Techniques, Humans, Molecular Structure, Niacin metabolism, Nicotinic Agonists chemistry, Receptors, Nicotinic, Structure-Activity Relationship, ortho-Aminobenzoates chemistry, Models, Molecular, Nicotinic Agonists chemical synthesis, Nicotinic Agonists pharmacology, Receptors, G-Protein-Coupled agonists, ortho-Aminobenzoates chemical synthesis, ortho-Aminobenzoates pharmacology
Abstract

A homology model of the nicotinic acid receptor GPR109A was constructed based on the X-ray crystal structure of bovine rhodopsin. An HTS hit was docked into the homology model. Characterization of the binding pocket by a grid-based surface calculation of the docking model suggested that a larger hydrophobic body plus a polar tail would improve interaction between the ligand and the receptor. The designed compounds were synthesized, and showed significantly improved binding affinity and activation of GPR109A.

Published
2008
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5. Discovery of orally bioavailable and novel urea agonists of the high affinity niacin receptor GPR109A.

Author

Shen HC, Szymonifka MJ, Kharbanda D, Deng Q, Carballo-Jane E, Wu KK, Wu TJ, Cheng K, Ren N, Cai TQ, Taggart AK, Wang J, Tong X, Waters MG, Hammond ML, Tata JR, and Colletti SL

Subjects
Animals, Combinatorial Chemistry Techniques, Humans, Male, Mice, Models, Animal, Molecular Structure, Receptors, Nicotinic, Structure-Activity Relationship, Vasodilation drug effects, Niacin pharmacology, Receptors, G-Protein-Coupled agonists, Urea analogs & derivatives, Urea chemical synthesis, Urea chemistry, Urea pharmacokinetics
Abstract

A urea class of high affinity niacin receptor agonists was discovered. Compound 1a displayed good PK, better in vivo efficacy in reducing FFA in mouse than niacin, and no vasodilation in a mouse model. Compound 1q demonstrated equal affinity to GPR109A as niacin.

Published
2007
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6. Discovery of biaryl anthranilides as full agonists for the high affinity niacin receptor.

Author

Shen HC, Ding FX, Luell S, Forrest MJ, Carballo-Jane E, Wu KK, Wu TJ, Cheng K, Wilsie LC, Krsmanovic ML, Taggart AK, Ren N, Cai TQ, Deng Q, Chen Q, Wang J, Wolff MS, Tong X, Holt TG, Waters MG, Hammond ML, Tata JR, and Colletti SL

Subjects
Amides chemical synthesis, Amides pharmacokinetics, Amides pharmacology, Animals, Aryl Hydrocarbon Hydroxylases antagonists & inhibitors, Binding, Competitive, CHO Cells, Cricetinae, Cricetulus, Cytochrome P-450 CYP2C8, Cytochrome P-450 CYP2C9, Humans, In Vitro Techniques, Mice, Microsomes, Liver metabolism, Radioligand Assay, Receptors, Nicotinic, Structure-Activity Relationship, ortho-Aminobenzoates pharmacokinetics, ortho-Aminobenzoates pharmacology, Receptors, G-Protein-Coupled agonists, ortho-Aminobenzoates chemical synthesis
Abstract

Biaryl anthranilides are reported as potent and selective full agonists for the high affinity niacin receptor GPR109A. The SAR presented outlines approaches to reduce serum shift and both CYPCYP2C8 and CYP2C9 liabilities, while improving PK and maintaining excellent receptor activity. Compound 2i exhibited good in vivo antilipolytic efficacy while providing a significantly improved therapeutic index over vasodilation (flushing) with respect to niacin in the mouse model.

Published
2007
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7. The discovery of potent antagonists of NPBWR1 (GPR7)

Author

Dorina Trusca, Feroze Ujjainwalla, Ying Lei, Richard G. Ball, Zhiqiang Guo, Jerry Di Salvo, Deng Qiaolin, F. Anthony Romero, Jenna L. Terebetski, Nicholas B. Hastings, Ming Wang, Remond Moningka, and Vincent Tong

Subjects
Models, Molecular, Receptors, Neuropeptide, Benzylamines, Stereochemistry, Clinical Biochemistry, Pharmaceutical Science, Stereoisomerism, Crystallography, X-Ray, Biochemistry, Piperazines, Receptors, G-Protein-Coupled, chemistry.chemical_compound, Mice, Structure-Activity Relationship, Drug Discovery, Structure–activity relationship, Animals, Humans, Receptor, Molecular Biology, Piperazine, G protein-coupled receptor, Dose-Response Relationship, Drug, Molecular Structure, Chemistry, Ligand binding assay, Organic Chemistry, Antagonist, Small molecule, Molecular Medicine
Abstract

The synthesis and evaluation of small molecule antagonists of the G protein-coupled receptor NPBWR1 (GPR7) are reported for the first time. [4-(5-Chloropyridin-2-yl)piperazin-1-yl][(1S,2S,4R)-4-{[(1R)-1-(4-methoxyphenyl)ethyl]amino}-2-(thiophen-3-yl)cyclohexyl]methanone (1) emerged as a hit from a high-throughput screen. Examination of substituents that focused on replacing the 5-chloropyridine and 4-methoxybenzylamino groups of 1 led to the identification of compounds that exhibited subnanomolar potencies as low as 660pM (9k) in the functional assay and 200pM in the binding assay (9i).

Published
2011

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