Potent biphenyl- and 3-phenyl pyridine-based inhibitors of acetyl-CoA carboxylase

Tasir S Haque; Ningning Liang; Rajasree Golla; Ramakrishna Seethala; Zhengping Ma; William R Ewing; Christopher B Cooper; Mary Ann Pelleymounter; Michael A Poss; Dong Cheng

doi:10.1016/j.bmcl.2009.08.077

Potent biphenyl- and 3-phenyl pyridine-based inhibitors of acetyl-CoA carboxylase

Bioorg Med Chem Lett. 2009 Oct 15;19(20):5872-6. doi: 10.1016/j.bmcl.2009.08.077. Epub 2009 Aug 26.

Authors

Tasir S Haque¹, Ningning Liang, Rajasree Golla, Ramakrishna Seethala, Zhengping Ma, William R Ewing, Christopher B Cooper, Mary Ann Pelleymounter, Michael A Poss, Dong Cheng

Affiliation

¹ Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543-4000, USA. tasir.haque@bms.com

PMID: 19740659
DOI: 10.1016/j.bmcl.2009.08.077

Abstract

We report the synthesis and enzymatic evaluation of potent inhibitors of acetyl-CoA carboxylases (ACCs) containing biphenyl or 3-phenyl pyridine cores. These compounds inhibit both ACC1 and ACC2, or are moderately selective for either enzyme, depending on side chain substitution. Typical activities of the most potent compounds in this class are in the low double-digit to single-digit nanomolar range in in vitro assays using human ACC1 and ACC2 enzymes.

MeSH terms

Acetyl-CoA Carboxylase / antagonists & inhibitors
Acetyl-CoA Carboxylase / metabolism
Anti-Obesity Agents / chemical synthesis
Anti-Obesity Agents / chemistry*
Anti-Obesity Agents / pharmacology
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry*
Enzyme Inhibitors / pharmacology
Humans
Pyridines / chemical synthesis
Pyridines / chemistry*
Pyridines / pharmacology
Stereoisomerism
Structure-Activity Relationship

Substances

Anti-Obesity Agents
Enzyme Inhibitors
Pyridines
ACACB protein, human
Acetyl-CoA Carboxylase