2. Academic Validation
  3. 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

  • Bioorg Med Chem. 2013 Sep 1;21(17):5081-97. doi: 10.1016/j.bmc.2013.06.045.
Robert L Dow 1,  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
Affiliations

Affiliation

  • 1 PharmaTherapeutics Research & Development, Pfizer Inc., 620 Memorial Drive, Cambridge, MA 02139, United States. robert.l.dow@pfizer.com
PMID: 23871442 DOI: 10.1016/j.bmc.2013.06.045
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.

Keywords

Carboxylic acid bioisotere; DGAT-1; Diabetes; Obesity; Passive permeability; Polar surface area.

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