Discovery of small molecule isozyme non-specific inhibitors of mammalian acetyl-CoA carboxylase 1 and 2.

Autor: Corbett JW; Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA. jmc1983mac@gmail.com, Freeman-Cook KD, Elliott R, Vajdos F, Rajamohan F, Kohls D, Marr E, Zhang H, Tong L, Tu M, Murdande S, Doran SD, Houser JA, Song W, Jones CJ, Coffey SB, Buzon L, Minich ML, Dirico KJ, Tapley S, McPherson RK, Sugarman E, Harwood HJ Jr, Esler W
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2010 Apr 01; Vol. 20 (7), pp. 2383-8. Date of Electronic Publication: 2009 Apr 24.
DOI: 10.1016/j.bmcl.2009.04.091
Abstrakt: 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.
(2010 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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