Discovery of small molecule isozyme non-specific inhibitors of mammalian acetyl-CoA carboxylase 1 and 2 |
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| Authors: | Jeffrey W. Corbett Kevin D. Freeman-Cook Richard Elliott Felix Vajdos Francis Rajamohan Darcy Kohls Eric Marr Hailong Zhang Liang Tong Meihua Tu Sharad Murdande Shawn D. Doran Janet A. Houser Wei Song Christopher J. Jones Steven B. Coffey Leanne Buzon Martha L. Minich Kenneth J. Dirico Susan Tapley William Esler |
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| Affiliation: | 1. Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA;2. Columbia University, New York, NY 10027, USA |
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| Abstract: | 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. |
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