11β-羟基类固醇脱氢酶1型的N-（吡啶-2-基）芳基磺酰胺抑制剂：PF-915275的发现。
N-(Pyridin-2-yl) arylsulfonamide inhibitors of 11beta-hydroxysteroid dehydrogenase type 1: Discovery of PF-915275.
作者信息
Siu Michael, Johnson Theodore O, Wang Yong, Nair Sajiv K, Taylor Wendy D, Cripps Stephan J, Matthews Jean J, Edwards Martin P, Pauly Thomas A, Ermolieff Jacques, Castro Arturo, Hosea Natilie A, LaPaglia Amy, Fanjul Andrea N, Vogel Jennifer E
机构信息
Discovery Chemistry, Pfizer Global Research and Development, 10770 Science Center Drive, San Diego, CA 92121, United States.
出版信息
Bioorg Med Chem Lett. 2009 Jul 1;19(13):3493-7. doi: 10.1016/j.bmcl.2009.05.011. Epub 2009 May 7.
N-(Pyridin-2-yl) arylsulfonamides are identified as inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1), an enzyme that catalyzes the reduction of the glucocorticoid cortisone to cortisol. Dysregulation of glucocorticoids has been implicated in the pathogenesis of diabetes and the metabolic syndrome. In this Letter, we present the development of an initial lead to an efficient ligand with improved physiochemical properties using a deletion strategy. This strategy allowed for further optimization of potency leading to the discovery of the clinical candidate PF-915275.
N-（吡啶-2-基）芳基磺酰胺被鉴定为11β-羟基类固醇脱氢酶1型（11βHSD1）的抑制剂，该酶催化糖皮质激素可的松还原为皮质醇。糖皮质激素失调与糖尿病和代谢综合征的发病机制有关。在本信函中，我们介绍了使用缺失策略将最初的先导化合物开发为具有改善物理化学性质的高效配体的过程。该策略使效力得以进一步优化，从而发现了临床候选药物PF-915275。
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