| Title | Sulfoximine-substituted trifluoromethylpyrimidine analogs as inhibitors of proline-rich tyrosine kinase 2 (PYK2) show reduced hERG activity. | | Author(s) | Walker DP, Zawistoski MP, McGlynn MA, Li JC, Kung DW, Bonnette PC, Baumann A, Buckbinder L, Houser JA, Boer J, Mistry A, Han S, Guzman-Perez LX | | Institution | Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA. | | Source | Bioorg Med Chem Lett 2009 Apr 24. | | 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. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 19428251 |
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