Design and synthesis of novel spirocyclic carboxylic acids as potent and orally bioavailable DGAT1 inhibitors and their biological evaluation. (15th April 2022)

• Record Type: Journal Article
• Authors: Koul, Summon; Kurhade, Suresh; Bhosale, Sandeep; Naik, Keshav; Salunkhe, Videsh; Ravula, Sudhir; Punde, Prasad; Velayutham, Ravikumar; Tiwari, Atul; Ahl, Daniela; Malkapuram, Srividya; Mudagala, Vamsi; Raje, Amol; Umrani, Dhananjay; Tambe, Suhas; Patil, Poonam; Singh, Umesh; Bhuniya, Debnath; Hariharan, Narayanan; Mookhtiar, Kasim
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 62(2022)
• Publication Date: 2022-04-15
• Subjects: Spirocyclic -- Azaspiro -- DGAT1 -- Triglycerides -- Diabetes -- Pharmacophore; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2022.128632
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: A series of novel spirocyclic DGAT1 inhibitors containing the oxadiazole motif were designed and synthesized for biological evaluation. Several compounds exhibited potent diacylglycerol acyltransferase 1 (DGAT1) inhibitory activity. Optimization of the series led to the identification of five lead compounds 8, 9, 10, 11 and 12 that showed excellent in-vitro activity with IC50 values ranging from 7 to 20 nM against human DGAT1. All compounds demonstrated good druggability as well as microsomal stability and safety profiles such as hERG and CYP. Compound 12 significantly reduced plasma triglyceride levels in-vivo in the mouse model of acute lipid challenge. Significant reduction in plasma TG excursion was observed, thus indicating DGAT1 inhibition in-vivo.