Referenced in: none

Automatically associated channels: Kv11.1

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

Authors: Daniel P Walker, Michael P Zawistoski, Molly A McGlynn, Jian-Cheng Li, Daniel W Kung, Peter C Bonnette, Amy Baumann, Leonard Buckbinder, Janet A Houser, Jason Boer, Anil Mistry, Seungil Han, Li Xing, Angel Guzman-Perez

Journal, date & volume: Bioorg. Med. Chem. Lett., 2009 Jun 15 , 19, 3253-8

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/19428251

Abstract
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.