Details

Autor(en) / Beteiligte

• Liu, Jiwen (Jim)
• Wang, Yingcai
• Ma, Zhihua
• Schmitt, Mike
• Zhu, Liusheng
• Brown, Sean P
• Dransfield, Paul J
• Sun, Ying
• Sharma, Rajiv
• Guo, Qi
• Zhuang, Run
• Zhang, Jane
• Luo, Jian
• Tonn, George R
• Wong, Simon
• Swaminath, Gayathri
• Medina, Julio C
• Lin, Daniel C.-H
• Houze, Jonathan B

Titel

Optimization of GPR40 Agonists for Type 2 Diabetes

Ist Teil von

• ACS medicinal chemistry letters, 2014-05, Vol.5 (5), p.517-521

Ort / Verlag

United States: American Chemical Society

Erscheinungsjahr

2014

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• GPR40 (FFA1 and FFAR1) has gained significant interest as a target for the treatment of type 2 diabetes. TAK-875 (1), a GPR40 agonist, lowered hemoglobin A1c (HbA1c) and lowered both postprandial and fasting blood glucose levels in type 2 diabetic patients in phase II clinical trials. We optimized phenylpropanoic acid derivatives as GPR40 agonists and identified AMG 837 (2) as a clinical candidate. Here we report our efforts in searching for structurally distinct back-ups for AMG 837. These efforts led to the identification of more polar GPR40 agonists, such as AM-4668 (10), that have improved potency, excellent pharmacokinetic properties across species, and minimum central nervous system (CNS) penetration.