Discovery of a second generation agonist of the orphan G-protein coupled receptor GPR119 with an improved profile

被引：49

作者：

Semple, Graeme ^{[1
]}

Lehmann, Juerg ^{[1
]}

Wong, Amy ^{[1
]}

Ren, Albert ^{[1
]}

Bruce, Marc ^{[1
]}

Shin, Young-Jun ^{[1
]}

Sage, Carleton R. ^{[1
]}

Morgan, Michael ^{[2
]}

Chen, Wei-Chao ^{[2
]}

Sebring, Kristen ^{[3
]}

Chu, Zhi-Liang ^{[3
]}

Leonard, James N. ^{[3
]}

Al-Shamma, Hussein ^{[3
]}

Grottick, Andrew J. ^{[3
]}

Du, Fuyong ^{[4
]}

Liang, Yin ^{[4
]}

Demarest, Keith ^{[4
]}

Jones, Robert M. ^{[1
]}

机构：

[1] Arena Pharmaceut, Med Chem, San Diego, CA 92121 USA

[2] Arena Pharmaceut, DMPK, San Diego, CA 92121 USA

[3] Arena Pharmaceut, Discovery Biol, San Diego, CA 92121 USA

[4] Johnson & Johnson Pharmaceut Res & Dev LLC, Spring House, PA 19477 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2012年 / 22卷 / 04期

关键词：

GPR119; GPCR; Diabetes; Lead optimization; GLYCEMIC CONTROL; G-PROTEIN-COUPLED-RECEPTOR-119; RELEASE; POTENT;

D O I：

10.1016/j.bmcl.2011.12.092

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The design and synthesis of a second generation GPR119-agonist clinical candidate for the treatment of diabetes is described. Compound 16 (APD597, JNJ-38431055) was selected for preclinical development based on a good balance between agonist potency, intrinsic activity and in particular on its good solubility and reduced drug-drug interaction potential. In addition, extensive in vivo studies showed a more favorable metabolic profile that may avoid the generation of long lasting metabolites with the potential to accumulate in clinical studies. (C) 2012 Elsevier Ltd. All rights reserved.

引用

页码：1750 / 1755

页数：6

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