Discovery of Phenylpropanoic Acid Derivatives Containing Polar Functionalities as Potent and Orally Bioavailable G Protein-Coupled Receptor 40 Agonists for the Treatment of Type 2 Diabetes

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• 作者：Satoshi Mikami ; Shuji Kitamura ; Nobuyuki Negoro ; Shinobu Sasaki ; Masami Suzuki ; Yoshiyuki Tsujihata ; Takeshi Miyazaki ; Ryo Ito ; Nobuhiro Suzuki ; Junichi Miyazaki ; Takashi Santou ; Naoyuki Kanzaki ; Miyuki Funami ; Toshimasa Tanaka ; Tsuneo Yasuma ; Yu Momose
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：April 26, 2012
• 年：2012
• 卷：55
• 期：8
• 页码：3756-3776
• 全文大小：689K
• 年卷期：v.55,no.8(April 26, 2012)
• ISSN：1520-4804

文摘

As part of a program to identify potent GPR40 agonists with drug-like properties suitable for clinical development, the incorporation of polar substituents was explored with the intention of decreasing the lipophilicity of our recently disclosed phenylpropanoic acid derivative 1. This incorporation would allow us to mitigate the cytotoxicity issues observed with compound 1 and enable us to move away from the multifunctional free fatty acid-like structure. Substitutions on the 2鈥?6鈥?dimethylbiphenyl ring were initially undertaken, which revealed the feasibility of introducing polar functionalities at the biphenyl 4鈥?position. Further optimization of this position and the linker led to the discovery of several 4鈥?alkoxybiphenyl derivatives, which showed potent GPR40 agonist activities with the best balance in terms of improved cytotoxicity profiles and favorable pharmacokinetic properties. Among them, 3-{2-fluoro-4-[({4鈥?[(4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy]-2鈥?6鈥?dimethylbiphenyl-3-yl}methyl)amino]phenyl}propanoic acid (35) exhibited a robust plasma glucose-lowering effect and insulinotropic action during an oral glucose tolerance test in rats with impaired glucose tolerance.