Optimization of a novel series of N-phenylindoline-5-sulfonamide-based acyl CoA:monoacylglycerol acyltransferase-2 inhibitors: Mitigation of CYP3A4 time-dependent inhibition and phototoxic liabilities.

Abstract

Acyl CoA:monoacylglycerol acyltransferase-2 (MGAT2) has emerged as a potential peripheral target for the treatment of obesity and metabolic disorders. We previously identified a novel series of N-phenylindoline-5-sulfonamide derivatives exemplified by 2 as potent and orally bioavailable MGAT2 inhibitors. Despite its attractive potency, further assessment revealed that this compound exhibited time-dependent inhibition (TDI) of cytochrome P450 3A4 (CYP3A4). To remove the undesirable CYP3A4 TDI activity, structural modification was focused on the 2,4-difluoroaniline moiety on the basis of the assumption that this moiety would be involved in mechanism-based inhibition of CYP3A4 via oxidative metabolism. This led to the finding that the introduction of 4-chloro-2,6-difluoroaniline significantly improved CYP3A4 TDI risk. Further optimization resulted in the discovery of N-(4-chloro-2,6-difluorophenyl)-1-{5-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]pyrimidin-2-yl}-7-(2-oxopyrrolidin-1-yl)-2,3-dihydro-1H-indole-5-sulfonamide (27c) with potent MGAT2 inhibitory activity (IC50=7.8 nM) and excellent ADME-Tox profiles including metabolic stability, oral bioavailability, and CYP3A4 TDI. In a mouse oral fat tolerance test, compound 27c effectively and dose-dependently suppressed the elevation of plasma triacylglycerol levels after oral administration at doses of 1 and 3mg/kg. We also discuss mitigation of the phototoxic liability of biaryl derivatives on the basis of the HOMO-LUMO gap hypothesis during the course of optimization efforts.

• Authors: Kenjiro Sato, Hiroki Takahagi, Osamu Kubo, Kousuke Hidaka, Takeshi Yoshikawa, Masahiro Kamaura, Masanori Nakakariya, Nobuyuki Amano, Ryutaro Adachi, Toshiyuki Maki, Kazumi Take, Shiro Takekawa, Tomoyuki Kitazaki, Tsuyoshi Maekawa
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 23 Issue 15 Pg. 4544-4560 (Aug 01 2015) ISSN: 1464-3391 [Electronic] England
• PMID: 26100443 (Publication Type: Journal Article)
• Copyright: Copyright © 2015 Elsevier Ltd. All rights reserved.

Chemical References

• Enzyme Inhibitors
• Cytochrome P-450 CYP3A
• Acyltransferases
• 2-acylglycerol O-acyltransferase

Topics

• Acyltransferases (antagonists & inhibitors)
• Animals
• Cytochrome P-450 CYP3A (drug effects)
• Enzyme Inhibitors (chemistry, pharmacology)
• Mice