Discovery of pyrrolopyridazines as novel DGAT1 inhibitors

被引：27

作者：

Fox, Brian M. ^{[1
]}

Iio, Kiyosei ^{[2
]}

Li, Kexue ^{[1
]}

Choi, Rebeka ^{[1
]}

Inaba, Takashi ^{[2
]}

Jackson, Simon ^{[1
]}

Sagawa, Shoichi ^{[2
]}

Shan, Bei ^{[1
]}

Tanaka, Masahiro ^{[2
]}

Yoshida, Atsuhito ^{[2
]}

Kayser, Frank ^{[1
]}

机构：

[1] Amgen Inc, Amgen S San Francisco, San Francisco, CA 94080 USA

[2] Japan Tobacco Inc, Cent Pharmaceut Res Inst, Osaka 5691125, Japan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2010年 / 20卷 / 20期

关键词：

DGAT1; inhibitors; Pyrrolopyridazines; Acyl CoA: diacylglycerol acyltransferase; COA-DIACYLGLYCEROL ACYLTRANSFERASE; TRIGLYCERIDE SYNTHESIS; OBESITY; CLONING; RESISTANCE; INSULIN; FAMILY; TARGET;

D O I：

10.1016/j.bmcl.2010.08.066

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

new structural class of DGAT1 inhibitors was discovered and the structure-activity relationship was explored. The pyrrolotriazine core of the original lead molecule was changed to a pyrrolopyridazine core providing an increase in potency. Further exploration resulted in optimization of the propyl group at C7 and the discovery that the ester at C6 could be replaced by five-membered heterocyclic rings. The analogs prepared have DGAT1 IC(50) values ranging from >10 mu M to 48 nM. (c) 2010 Elsevier Ltd. All rights reserved.

引用

页码：6030 / 6033

页数：4

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