原创力文档discovery of orally active hepatoselective glucokinase activators for treatment of type ii diabetes mellitus：（发现口服hepatoselective葡糖激酶活化剂治疗ii型糖尿病）.pdfVIP
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discovery of orally active hepatoselective glucokinase activators for treatment of type ii diabetes mellitus：（发现口服hepatoselective葡糖激酶活化剂治疗ii型糖尿病）
Bioorganic Medicinal Chemistry Letters 27 (2017) 2063–2068
Contents lists available at ScienceDirect
Bioorganic Medicinal Chemistry Letters
journal homepage: www.else /locate/bmcl
Discovery of orally active hepatoselective glucokinase activators for
treatment of Type II Diabetes Mellitus
Jiayi Xu ⇑, Songnian Lin ⇑, Robert W. Myers, Maria E. Trujillo, Michele J. Pachanski, Sunita Malkani,
Hsuan-shen Chen, Zhesheng Chen, Brian Campbell, George J. Eiermann, Nadine Elowe, Brian T. Farrer,
Wen Feng, Qinghong Fu, Roman Kats-Kagan, Michael Kavana, Daniel R. McMasters, Kaushik Mitra,
Xinchun Tong, Libo Xu, Fengqi Zhang, Rui Zhang, George H. Addona, Joel P. Berger, Bei Zhang,
Emma R. Parmee
Discovery, Preclinical and Early Development, Merck Co., Inc., 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA
a r t i c l e i n f o a b s t r a c t
Article history: Systemically acting glucokinase activators (GKA) have been demonstrated in clinical trials to effectively
Received 16 September 2016 lower blood glucose in patients with type II diabetes. However, mechanism-based hypoglycemia is a
Revised 26 October 2016 major adverse effect that limits the therapeutic potential of these agents. We hypothesized that the pre-
Accepted 28 October 2016
dominant mechanism leading to hypoglycemia is GKA-induced excessive insulin secretion from pancre-
Available online 31 October 2016
atic b-cells at (sub-)euglycemic levels. We further hypothesized that restricting GK activation to
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