Journal article
Utilization of an Active Site Mutant Receptor for the Identification of Potent and Selective Atypical 5-HT2C Receptor Agonists
Journal of medicinal chemistry, v 60(14), pp 6166-6190
27 Jul 2017
PMID: 28635286
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Agonism of the 5-HT2C receptor represents one of the most well-studied and clinically proven mechanisms for pharmacological weight reduction. Selectivity over the closely related 5-HT2A and 5-HT2B 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-HT2C receptor to identify atypical agonist structures. We additionally report the discovery and optimization of a novel class of nonbasic heterocyclic amide agonists of 5-HT2C. SAR. investigations around the screening hits provided a diverse set of potent agonists at 5-HT2C with high selectivity over the related 5-HT2A and 5-HT2B 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-Apyridazin-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-HT2C antagonist.
Metrics
Details
- Title
- Utilization of an Active Site Mutant Receptor for the Identification of Potent and Selective Atypical 5-HT2C Receptor Agonists
- Creators
- Joseph Carpenter - Bristol-Myers Squibb (United States)Ying Wang - Bristol-Myers Squibb (United States)Gang Wu - Bristol-Myers Squibb (United States)Jianxin Feng - Bristol-Myers Squibb (United States)Xiang-Yang YeChristian L. Morales - Bristol-Myers Squibb (United States)Matthias Broekema - Bristol-Myers Squibb (United States)Karen A. Rossi - Bristol-Myers Squibb (United States)Keith J. Miller - Bristol-Myers Squibb (United States)Brian J. Murphy - Bristol-Myers Squibb (United States)Ginger Wu - Bristol-Myers Squibb (United States)Sarah E. Malmstrom - Bristol-Myers Squibb (United States)Anthony V. Azzara - Bristol-Myers Squibb (United States)Philip M. Sher - Bristol-Myers Squibb (United States)John M. Fevig - Bristol-Myers Squibb (United States)Andrew Alt - Bristol-Myers Squibb (United States)Robert L. Bertekap - Bristol-Myers Squibb (United States)Mary Jane Cullen - Bristol-Myers Squibb (United States)Timothy M. Harper - Bristol-Myers Squibb (United States)Kimberly Foster - Bristol-Myers Squibb (United States)Emily Luk - Bristol-Myers Squibb (United States)Qian Xiang - Bristol-Myers Squibb (United States)Mary F. Grubb - Bristol-Myers Squibb (Germany)Jeffrey A. Robl - Bristol-Myers Squibb (United States)Dean A. Wacker - Bristol-Myers Squibb (United States)
- Publication Details
- Journal of medicinal chemistry, v 60(14), pp 6166-6190
- Publisher
- Amer Chemical Soc
- Number of pages
- 25
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pharmacology and Physiology
- Web of Science ID
- WOS:000406727700015
- Scopus ID
- 2-s2.0-85026354400
- Other Identifier
- 991021903116304721
UN Sustainable Development Goals (SDGs)
This publication has contributed to the advancement of the following goals:
InCites Highlights
Data related to this publication, from InCites Benchmarking & Analytics tool:
- Web of Science research areas
- Chemistry, Medicinal