Discovery of a potent M5 antagonist with improved clearance profile. Part 2: Pyrrolidine amide-based antagonists. (15th December 2022)

• Record Type: Journal Article
• Authors: Orsi, Douglas L.; Felts, Andrew S.; Rodriguez, Alice L.; Vinson, Paige N.; Cho, Hyekyung P.; Chang, Sichen; Blobaum, Anna L.; Niswender, Colleen M.; Conn, P. Jeffrey; Jones, Carrie K.; Lindsley, Craig W.; Han, Changho
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 78(2022)
• Publication Date: 2022-12-15
• Subjects: Muscarinic acetylcholine receptor 5 -- mAChR -- M5 -- Antagonist; ADME Absorption, Distribution, Metabolism, and Excretion -- DIPEA N, N-Diisopropylethylamine -- DMPK Drug metabolism and pharmacokinetics -- ER Efflux ratio -- HATU 1-[Bis(dimethylamino)methylene]-1H-1, 2, 3-triazolo[4, 5-b]pyridinium 3-oxide hexafluorophosphate -- HTS High throughput screening -- SAR Structure-activity relationship; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2022.129021
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: This Letter describes our ongoing effort to improve the clearance of selective M5 antagonists. Herein, we report the replacement of the previously disclosed piperidine amide (4, disclosed in Part 1) with a pyrrolidine amide core. Several compounds within this series provided good potency, subtype selectivity, and low to moderate clearance profiles. Interestingly, the left-hand side SAR for this series diverged from our earlier efforts.