(3,3-Difluoro-pyrrolidin-1-yl)-[(2S,4S)-(4-(4-pyrimidin-2-yl-piperazin-1-yl)-pyrrolidin-2-yl]-methanone: A potent, selective, orally active dipeptidyl peptidase IV inhibitor,Bioorganic & Medicinal Chemistry Letters

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(3,3-Difluoro-pyrrolidin-1-yl)-[(2S,4S)-(4-(4-pyrimidin-2-yl-piperazin-1-yl)-pyrrolidin-2-yl]-methanone: A potent, selective, orally active dipeptidyl peptidase IV inhibitor
Bioorganic & Medicinal Chemistry Letters ( IF 2.5 ) Pub Date : 2009-02-13 , DOI: 10.1016/j.bmcl.2009.02.041
Mark J. Ammirati , Kim M. Andrews , David D. Boyer , Anne M. Brodeur , Dennis E. Danley , Shawn D. Doran , Bernard Hulin , Shenping Liu , R. Kirk McPherson , Stephen J. Orena , Janice C. Parker , Jana Polivkova , Xiayang Qiu , Carolyn B. Soglia , Judith L. Treadway , Maria A. VanVolkenburg , Donald C. Wilder , David W. Piotrowski

A series of 4-substituted proline amides was synthesized and evaluated as inhibitors of dipeptidyl pepdidase IV for the treatment of type 2 diabetes. (3,3-Difluoro-pyrrolidin-1-yl)-[(2S,4S)-(4-(4-pyrimidin-2-yl-piperazin-1-yl)-pyrrolidin-2-yl]-methanone (5) emerged as a potent (IC₅₀= 13 nM) and selective compound, with high oral bioavailability in preclinical species and low plasma protein binding. Compound 5, PF-00734200, was selected for development as a potential new treatment for type 2 diabetes.

中文翻译：

（3,3-二氟-吡咯烷-1-基）-[（2 S，4 S）-（4-（4-嘧啶-2-基-哌嗪-1-基）-吡咯烷-2-基]-甲酮：一种有效的，选择性的，口服活性的二肽基肽酶IV抑制剂

合成了一系列4-取代的脯氨酸酰胺，并将其评估为二肽基肽酶IV的抑制剂，用于治疗2型糖尿病。（3,3-二氟-吡咯烷-1-基）-[（2 S，4 S）-（4-（4-嘧啶-2-基-哌嗪-1-基）-吡咯烷-2-基]-甲酮（5）成为一种有效的（IC ₅₀ = 13 nM）选择性化合物，在临床前物种中具有较高的口服生物利用度，且血浆蛋白结合率低，选择了化合物5 PF-00734200作为潜在的2型新疗法进行开发糖尿病。

更新日期：2009-02-13

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