Journal article
Exploring monocyclic core: Discovery of pyrrol-2-one derivatives as a new series of potent MCHR1 antagonists with in vivo efficacy
European journal of medicinal chemistry, v 276, p116686
05 Oct 2024
PMID: 39053192
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
With an objective to improve the profiles of the 1st generation non-basic MCHR1 antagonists, a lean design approach of replacing the bicyclic thienopyrimidine core with a monocyclic pyrrol-2-one chemotype was examined in the context of reducing aromatic ring count, while also contemplating enhanced flexibility as a means of decreasing flat character. The new compounds exhibited potent antagonism up to the sub-nanomolar range, thereby implying that the monocyclic ring could effectively serve as an effective bioisostere of the bicyclic system. The prototype compound 2m offered benefits like improved potency, reduced half-life, and enhanced solubility, while also demonstrating >5% reduction in weight gain in rats, thereby providing proof-of-concept for this new class of compounds as anti-obesity agents.
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Details
- Title
- Exploring monocyclic core: Discovery of pyrrol-2-one derivatives as a new series of potent MCHR1 antagonists with in vivo efficacy
- Creators
- Murugaiah A. M. Subbaiah - Bristol-Myers Squibb (India)Umasankar Mandal - Bristol-Myers Squibb (India)Vidya Patankar - Bristol-Myers Squibb (India)Selvakumar Bhaskaran - Biocon Bristol Myers Squibb Res & Dev Ctr, Dept Med Chem, Biocon Pk,Bommasandra 4 Phase,Jigani Link Rd, Bangalore 560099, Karnataka, IndiaRavikumar Nutakki - Bristol-Myers Squibb (India)Bhadresh Rami - Bristol-Myers Squibb (India)Devang Praful Shah - Bristol-Myers Squibb (India)Shahe Mahammad - Biocon Bristol Myers Squibb Res & Dev Ctr, Dept Biopharmaceut, Biocon Pk,Bommasandra 4 Phase,Jigani Link Rd, Bangalore 560099, Karnataka, IndiaBrian J. Murphy - Bristol-Myers Squibb (United States)Christine Huang - Bristol-Myers Squibb (United States)Jeffrey A. Robl - Bristol-Myers Squibb (United States)William N. Washburn - Bristol-Myers Squibb (United States)
- Publication Details
- European journal of medicinal chemistry, v 276, p116686
- Publisher
- Elsevier
- Number of pages
- 11
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pharmacology and Physiology
- Web of Science ID
- WOS:001281121700001
- Scopus ID
- 2-s2.0-85199151113
- Other Identifier
- 991021903123804721
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- Collaboration types
- International collaboration
- Web of Science research areas
- Chemistry, Medicinal