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Defining the Key Pharmacophore Elements of PF-04620110: Discovery of a Potent, Orally-Active, Neutral DGAT-1 Inhibitor

Defining the Key Pharmacophore Elements of PF-04620110: Discovery of a Potent, Orally-Active, Neutral DGAT-1 Inhibitor

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, etc.

Bioorg Med Chem. 2013 Sep 1;21(17):5081-97.

PMID: 23871442

Abstract:

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP1109276892	PF-04620110		1109276-89-2	Price

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