Defining the key pharmacophore elements of PF-04620110: Discovery of a potent, orally-active, neutral DGAT-1 inhibitor
详细信息 查看全文
- 作者：Robert L. Dow ; Melissa P. Andrews ; Jian-Cheng Li ; E. Michael Gibbs ; Angel Guzman-Perez ; Jennifer L. LaPerle ; Qifang Li ; Dawn Mather ; Michael J. Munchhof ; Mark Niosi ; Leena Patel ; Christian Perreault ; Susan Tapley ; William J. Zavadoski
- 关键词：DGAT-1 ; Diabetes ; Obesity ; Passive permeability ; Carboxylic acid bioisotere ; Polar surface area
- 刊名：Bioorganic and Medicinal Chemistry
- 出版年：2013
- 出版时间：1 September, 2013
- 年：2013
- 卷：21
- 期：17
- 页码：5081-5097
- 全文大小：3954 K
文摘
DGAT-1 is an enzyme that catalyzes the final step in triglyceride synthesis. mRNA knockout experiments in rodent models suggest that inhibitors of this enzyme could be of value in the treatment of obesity and type II diabetes. The carboxylic acid-based DGAT-1 inhibitor 1 was advanced to clinical trials for the treatment of type 2 diabetes, despite of the low passive permeability of 1. Because of questions relating to the potential attenuation of distribution and efficacy of a poorly permeable agent, efforts were initiated to identify compounds with improved permeability. Replacement of the acid moiety in 1 with an oxadiazole led to the discovery of 52, which possesses substantially improved passive permeability. The resulting pharmacodynamic profile of this neutral DGAT-1 inhibitor was found to be similar to 1 at comparable plasma exposures.