Utilization of an Active Site Mutant Receptor for the Identification of Potent and Selective Atypical 5-HT2C Receptor Agonists

Joseph Carpenter; Ying Wang; Gang Wu; Jianxin Feng; Xiang-Yang Ye; Christian L Morales; Matthias Broekema; Karen A Rossi; Keith J Miller; Brian J Murphy; Ginger Wu; Sarah E Malmstrom; Anthony V Azzara; Philip M Sher; John M Fevig; Andrew Alt; Robert L Bertekap Jr; Mary Jane Cullen; Timothy M Harper; Kimberly Foster; Emily Luk; Qian Xiang; Mary F Grubb; Jeffrey A Robl; Dean A Wacker

doi:10.1021/acs.jmedchem.7b00385

Utilization of an Active Site Mutant Receptor for the Identification of Potent and Selective Atypical 5-HT_2C Receptor Agonists

J Med Chem. 2017 Jul 27;60(14):6166-6190. doi: 10.1021/acs.jmedchem.7b00385. Epub 2017 Jul 7.

Authors

Joseph Carpenter¹, Ying Wang¹, Gang Wu¹, Jianxin Feng¹, Xiang-Yang Ye¹, Christian L Morales¹, Matthias Broekema¹, Karen A Rossi¹, Keith J Miller¹, Brian J Murphy¹, Ginger Wu¹, Sarah E Malmstrom¹, Anthony V Azzara¹, Philip M Sher¹, John M Fevig¹, Andrew Alt¹, Robert L Bertekap Jr¹, Mary Jane Cullen¹, Timothy M Harper¹, Kimberly Foster¹, Emily Luk¹, Qian Xiang¹, Mary F Grubb¹, Jeffrey A Robl¹, Dean A Wacker¹

Affiliation

¹ Departments of Discovery Chemistry, Discovery Biology, Lead Evaluation, Computer-Assisted Drug Design, Discovery Toxicology, and Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Pharmaceutical Research Institute , P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.

PMID: 28635286
DOI: 10.1021/acs.jmedchem.7b00385

Abstract

Agonism of the 5-HT_2C receptor represents one of the most well-studied and clinically proven mechanisms for pharmacological weight reduction. Selectivity over the closely related 5-HT_2A and 5-HT_2B receptors is critical as their activation has been shown to lead to undesirable side effects and major safety concerns. In this communication, we report the development of a new screening paradigm that utilizes an active site mutant D134A (D3.32) 5-HT_2C receptor to identify atypical agonist structures. We additionally report the discovery and optimization of a novel class of nonbasic heterocyclic amide agonists of 5-HT_2C. SAR investigations around the screening hits provided a diverse set of potent agonists at 5-HT_2C with high selectivity over the related 5-HT_2A and 5-HT_2B receptor subtypes. Further optimization through replacement of the amide with a variety of five- and six-membered heterocycles led to the identification of 6-(1-ethyl-3-(quinolin-8-yl)-1H-pyrazol-5-yl)pyridazin-3-amine (69). Oral administration of 69 to rats reduced food intake in an ad libitum feeding model, which could be completely reversed by a selective 5-HT_2C antagonist.

MeSH terms

ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
ATP Binding Cassette Transporter, Subfamily G, Member 2 / genetics
Animals
Arginine / analogs & derivatives*
Arginine / chemical synthesis
Arginine / chemistry
Arginine / pharmacology
Brain / metabolism
Caco-2 Cells
Cell Membrane Permeability
Feeding Behavior / drug effects
Flavones / chemical synthesis
Flavones / chemistry*
Flavones / pharmacology
HEK293 Cells
Humans
Male
Membranes, Artificial
Mice, Knockout
Microsomes, Liver / metabolism
Mutation
Rats, Sprague-Dawley
Receptor, Serotonin, 5-HT2A / metabolism
Receptor, Serotonin, 5-HT2B / metabolism
Receptor, Serotonin, 5-HT2C / genetics
Receptor, Serotonin, 5-HT2C / metabolism*
Serotonin 5-HT2 Receptor Agonists / chemical synthesis
Serotonin 5-HT2 Receptor Agonists / chemistry*
Serotonin 5-HT2 Receptor Agonists / pharmacokinetics
Serotonin 5-HT2 Receptor Agonists / pharmacology
Structure-Activity Relationship

Substances

ATP Binding Cassette Transporter, Subfamily B, Member 1
ATP Binding Cassette Transporter, Subfamily G, Member 2
Abcg2 protein, mouse
Flavones
Membranes, Artificial
Receptor, Serotonin, 5-HT2A
Receptor, Serotonin, 5-HT2B
Receptor, Serotonin, 5-HT2C
Serotonin 5-HT2 Receptor Agonists
methyl (2-((7-((7-guanidino-4-(methoxyamino)-2,3-dioxoheptyl)oxy)-5-hydroxy-2-(4-methoxyphenyl)-8-(3-methylbut-2-en-1-yl)-4-oxo-4H-chromen-3-yl)oxy)acetyl)argininate
Arginine