Discovery of Small Molecule Isozyme Non-specific Inhibitors of Mammalian Acetyl-CoA Carboxylase 1 and 2

Journal Article · Thu Dec 31 23:00:00 EST 2009 · Bioorganic and Medicinal Chemistry Letters

DOI:https://doi.org/10.1016/j.bmcl.2009.04.091· OSTI ID:1019899

Corbett, J; Freeman-Cook, K; Elliott, R; Vajdos, F; Rajamohan, F; Kohls, D; Marr, E; Harwood, Jr, H; Esler, W

Screening Pfizer's compound library resulted in the identification of weak acetyl-CoA carboxylase inhibitors, from which were obtained rACC1 CT-domain co-crystal structures. Utilizing HTS hits and structure-based drug discovery, a more rigid inhibitor was designed and led to the discovery of sub-micromolar, spirochromanone non-specific ACC inhibitors. Low nanomolar, non-specific ACC-isozyme inhibitors that exhibited good rat pharmacokinetics were obtained from this chemotype.

• Research Organization: Brookhaven National Laboratory (BNL) National Synchrotron Light Source
• Sponsoring Organization: DOE - OFFICE OF SCIENCE
• DOE Contract Number: AC02-98CH10886
• OSTI ID: 1019899
• Report Number(s): BNL--95745-2011-JA
• Journal Information: Bioorganic and Medicinal Chemistry Letters, Journal Name: Bioorganic and Medicinal Chemistry Letters Journal Issue: 7 Vol. 20; ISSN 0960-894X
• Country of Publication: United States
• Language: English

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
99 GENERAL AND MISCELLANEOUS
CARBOXYLASE
DRUGS
MEDICINE
national synchrotron light source