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.
Walker
Daniel P
DP
Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA. daniel.p.walker@pfizer.com
Zawistoski
Michael P
MP
McGlynn
Molly A
MA
Li
Jian-Cheng
JC
Kung
Daniel W
DW
Bonnette
Peter C
PC
Baumann
Amy
A
Buckbinder
Leonard
L
Houser
Janet A
JA
Boer
Jason
J
Mistry
Anil
A
Han
Seungil
S
Xing
Li
L
Guzman-Perez
Angel
A
D000284:Administration, Oral; D000818:Animals; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism*; D051418:Focal Adhesion Kinase 2 / Q000037:antagonists & inhibitors*; D006801:Humans; D007097:Imines / Q000737:chemistry; D010024:Osteoporosis / Q000188:drug therapy; D018408:Patch-Clamp Techniques; D010627:Phenethylamines; D011743:Pyrimidines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D013449:Sulfonamides; D013450:Sulfones / Q000737:chemistry
D004791:Enzyme Inhibitors; D051638:Ether-A-Go-Go Potassium Channels; D007097:Imines; D010627:Phenethylamines; D011743:Pyrimidines; D013449:Sulfonamides; D013450:Sulfones; D051418:Focal Adhesion Kinase 2; C063533:dofetilide