2-({6-[(3R)-3-amino-3-methylpiperidine-1-yl]-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-d]pyrimidine-5-yl}methyl)-4-fluorobenzonitrile (DSR-12727): A potent, orally active dipeptidyl peptidase IV inhibitor without mechanism-based inactivatio

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• 作者：Yukihiro  ; Nishio  ; ;   ; ^{yukihiro-nishio@ds-pharma.co.jp} ; Hidenori  ; Kimura ; Naoyuki  ; Sawada ; Eiji  ; Sugaru ; Masakuni  ; Horiguchi ; Michiko  ; Ono ; Yudai  ; Furuta ; Mutsuko  ; Sakai ; Yumi  ; Masui ; Misato  ; Otani ; Takahiko  ; Hashizuka ; Yayoi  ; Honda ; Jiro  ; Deguchi ; Tsutomu  ; Nakagawa ; Hiroyuki  ; Nakahira
• 关键词：DPP IV inhibitors ; Mechanism-based inactivation
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2011
• 出版时间：15 September 2011
• 年：2011
• 卷：19
• 期：18
• 页码：5490-5499
• 全文大小：508 K

文摘

We report on the identification of 2-({6-[(3R)-3-amino-3-methylpiperidine-1-yl]-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-d]pyrimidine-5-yl}methyl)-4-fluorobenzonitrile (DSR-12727) (7a) as a potent and orally active DPP-4 inhibitor without mechanism-based inactivation of CYP3A. Compound 7a showed good DPP-4 inhibitory activity (IC₅₀ = 1.1 nM), excellent selectivity against related peptidases and other off-targets, good pharmacokinetic and pharmacodynamic profile, great in vivo efficacy in Zucker-fatty rat, and no safety concerns both in vitro and in vivo.