Discovery of 3-hydroxy-4-cyano-isoquinolines as novel, potent, and selective inhibitors of human 11¦Â-hydroxydehydrogenase 1 (11¦Â-HSD1)

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• 作者：Shung C.  ; Wu^a ;   ; ^{shung.wu@bms.com} ; David  ; Yoon^a ; Janice  ; Chin^c ; Katy  ; van Kirk^b ; Ramakrishna  ; Seethala^a ; Rajasree  ; Golla^a ; Bin  ; He^a ; Thomas  ; Harrity^a ; Lori K.  ; Kunselman^a ; Nathan N.  ; Morgan^a ; Randolph P.  ; Ponticiello^a ; Joseph R.  ; Taylor^a ; Rachel  ; Zebo^a ; Timothy W.  ; Harper^a ; Wenying  ; Li^b ; Mengmeng  ; Wang^a ; Lisa  ; Zhang^a ; Bogdan G.  ; Sleczka^b ; Akbar  ; Nayeem^a ; Steven  ; Sheriff^b ; Daniel M.  ; Camac^b ; Paul E.  ; Morin^b ; John G.  ; Everlof^b ; Yi-Xin  ; Li^a ; Cheryl A.  ; Ferraro^c ; Kasia  ; Kieltyka^c ; Wilson  ; Shou^c ; Marianne B.  ; Vath^c ; Tatyana A.  ; Zvyaga^c ; David A.  ; Gordon^a ; Jeffrey A.  ; Robl^a
• 关键词：Type 2 diabetes ; 11¦Â-HSD1 ; Inhibitors ; Hydroxyisoquinolines ; Cross-species activity
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2011
• 出版时间：15 November 2011
• 年：2011
• 卷：21
• 期：22
• 页码：6693-6698
• 全文大小：1217 K

文摘

Derived from the HTS hit 1, a series of hydroxyisoquinolines was discovered as potent and selective 11¦Â-HSD1 inhibitors with good cross species activity. Optimization of substituents at the 1 and 4 positions of the isoquinoline group in addition to the core modifications, with a special focus on enhancing metabolic stability and aqueous solubility, resulted in the identification of several compounds as potent advanced leads.