The development and SAR of pyrrolidine carboxamide 11β-HSD1 inhibitors

…, K Dress, M Edwards, B Cole, E Walters, C Loh…

Index: Cheng, Hengmiao; Hoffman, Jacqui; Le, Phuong; Nair, Sajiv K.; Cripps, Stephan; Matthews, Jean; Smith, Christopher; Yang, Michele; Kupchinsky, Stan; Dress, Klaus; Edwards, Martin; Cole, Bridget; Walters, Evan; Loh, Christine; Ermolieff, Jacques; Fanjul, Andrea; Bhat, Ganesh B.; Herrera, Jocelyn; Pauly, Tom; Hosea, Natilie; Paderes, Genevieve; Rejto, Paul Bioorganic and Medicinal Chemistry Letters, 2010 , vol. 20, # 9 p. 2897 - 2902

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Citation Number: 28

Abstract

The design and development of a series of highly selective pyrrolidine carboxamide 11β- HSD1 inhibitors are described. These compounds including PF-877423 demonstrated potent in vitro activity against both human and mouse 11β-HSD1 enzymes. In an in vivo assay, PF-877423 inhibited the conversion of cortisone to cortisol. Structure guided optimization effort yielded potent and stable 11β-HSD1 selective inhibitor 42.