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ID: ALA5143597
Journal: Bioorg Med Chem Lett
Title: Design and synthesis of novel spirocyclic carboxylic acids as potent and orally bioavailable DGAT1 inhibitors and their biological evaluation.
Authors: Koul S, Kurhade S, Bhosale S, Naik K, Salunkhe V, Ravula S, Punde P, Velayutham R, Tiwari A, Ahl D, Malkapuram S, Mudagala V, Raje A, Umrani D, Tambe S, Patil P, Singh U, Bhuniya D, Hariharan N, Mookhtiar K.
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.
CiteXplore: 35189320