Defining the key pharmacophore elements of PF-04620110: discovery of a potent, orally-active, neutral DGAT-1 inhibitor.

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.

Sulfoximine-substituted trifluoromethylpyrimidine analogs as inhibitors of proline-rich tyrosine kinase 2 (PYK2) show reduced hERG activity.

The synthesis, in vitro properties, and in vivo pharmacokinetics for a series of sulfoximine-substituted trifluoromethylpyrimidines as inhibitors of proline-rich tyrosine kinase, a target for the possible treatment of osteoporosis, are described. These compounds were prepared as surrogates of the corresponding sulfone compound 1. Sulfone 1 was an attractive PYK2 lead compound; however, subsequent studies determined this compound possessed high dofetilide binding, which is an early indicator of cardiovascular safety. Surprisingly, the corresponding sulfoximine analogs displayed significantly lower dofetilide binding, which, for N-methylsulfoximine (S)-14a, translated to lower activity in a patch clamp hERG K(+) ion channel screen. In addition, compound (S)-14a shows good oral exposure in a rat pharmacokinetic model.