Design and synthesis of novel spirocyclic carboxylic acids as potent and orally bioavailable DGAT1 inhibitors and their biological evaluation

Summon Koul; Suresh Kurhade; Sandeep Bhosale; Keshav Naik; Videsh Salunkhe; Sudhir Ravula; Prasad Punde; Ravikumar Velayutham; Atul Tiwari; Daniela Ahl; Srividya Malkapuram; Vamsi Mudagala; Amol Raje; Dhananjay Umrani; Suhas Tambe; Poonam Patil; Umesh Singh; Debnath Bhuniya; Narayanan Hariharan; Kasim Mookhtiar

doi:10.1016/j.bmcl.2022.128632

Design and synthesis of novel spirocyclic carboxylic acids as potent and orally bioavailable DGAT1 inhibitors and their biological evaluation

Bioorg Med Chem Lett. 2022 Apr 15:62:128632. doi: 10.1016/j.bmcl.2022.128632. Epub 2022 Feb 18.

Authors

Summon Koul¹, Suresh Kurhade², Sandeep Bhosale², Keshav Naik², Videsh Salunkhe², Sudhir Ravula², Prasad Punde², Ravikumar Velayutham², Atul Tiwari², Daniela Ahl², Srividya Malkapuram², Vamsi Mudagala², Amol Raje², Dhananjay Umrani², Suhas Tambe², Poonam Patil², Umesh Singh², Debnath Bhuniya², Narayanan Hariharan², Kasim Mookhtiar²

Affiliations

¹ Department of Discovery Chemistry, Discovery Biology and DMPK, Advinus Therapeutics. Ltd., Hinjewadi, Pune 411 057, India; School of Consciousness, Dr.Vishwanath Karad MIT World Peace University, Pune, Maharashtra 411038, India. Electronic address: summon.koul@mitwpu.edu.in.
² Department of Discovery Chemistry, Discovery Biology and DMPK, Advinus Therapeutics. Ltd., Hinjewadi, Pune 411 057, India.

PMID: 35189320
DOI: 10.1016/j.bmcl.2022.128632

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.

Keywords: Azaspiro; DGAT1; Diabetes; Pharmacophore; Spirocyclic; Triglycerides.

MeSH terms

Animals
Carboxylic Acids* / pharmacology
Diacylglycerol O-Acyltransferase* / antagonists & inhibitors
Disease Models, Animal
Drug Design
Enzyme Inhibitors* / pharmacology
Mice
Oxadiazoles / pharmacology
Triglycerides

Substances

Carboxylic Acids
Enzyme Inhibitors
Oxadiazoles
Triglycerides
Dgat1 protein, mouse
Diacylglycerol O-Acyltransferase