Discovery of piperidine-aryl urea-based stearoyl-CoA desaturase 1 inhibitors

Zhili Xin; Hongyu Zhao; Michael D Serby; Bo Liu; Mei Liu; Bruce G Szczepankiewicz; Lissa T J Nelson; Harriet T Smith; Tom S Suhar; Rich S Janis; Ning Cao; Heidi S Camp; Christine A Collins; Hing L Sham; Teresa K Surowy; Gang Liu

doi:10.1016/j.bmcl.2008.06.088

Discovery of piperidine-aryl urea-based stearoyl-CoA desaturase 1 inhibitors

Bioorg Med Chem Lett. 2008 Aug 1;18(15):4298-302. doi: 10.1016/j.bmcl.2008.06.088. Epub 2008 Jun 28.

Authors

Zhili Xin¹, Hongyu Zhao, Michael D Serby, Bo Liu, Mei Liu, Bruce G Szczepankiewicz, Lissa T J Nelson, Harriet T Smith, Tom S Suhar, Rich S Janis, Ning Cao, Heidi S Camp, Christine A Collins, Hing L Sham, Teresa K Surowy, Gang Liu

Affiliation

¹ Abbott Laboratories, Global Pharmaceutical Research and Development, 100 Abbott Road, Abbott Park, IL 60064, USA. zhili.xin@biogenidec.com

PMID: 18632269
DOI: 10.1016/j.bmcl.2008.06.088

Abstract

A series of structurally novel stearoyl-CoA desaturase1 (SCD1) inhibitors has been identified via molecular scaffold manipulation. Preliminary structure-activity relationship (SAR) studies led to the discovery of potent, and orally bioavailable piperidine-aryl urea-based SCD1 inhibitors. 4-(2-Chlorophenoxy)-N-[3-(methyl carbamoyl)phenyl]piperidine-1-carboxamide 4c exhibited robust in vivo activity with dose-dependent desaturation index lowering effects.

MeSH terms

Dose-Response Relationship, Drug
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Molecular Structure
Piperidines / chemical synthesis
Piperidines / chemistry
Piperidines / pharmacology*
Stearoyl-CoA Desaturase / antagonists & inhibitors*
Structure-Activity Relationship
Substrate Specificity
Urea / analogs & derivatives*
Urea / chemical synthesis*
Urea / chemistry
Urea / pharmacology*

Substances

4-(2-chlorophenoxy)-N-(3-(methyl carbamoyl)phenyl)piperidine-1-carboxamide
Enzyme Inhibitors
Piperidines
Urea
Stearoyl-CoA Desaturase