Novel pyrazolo[1,5-a]pyrimidines as c-Src kinase inhibitors that reduce IKr channel blockade.
To improve the in vitro potency of the c-Src inhibitor 1a and to address its hERG liability, a structure-activity study was carried out, focusing on two regions of the lead compound. The blockade of the delayed cardiac current rectifier K(+) (I(Kr)) channel was overcome by replacing the ethylenediamino group with an amino alcohol group at the 7-position. In addition, modifying the substituents at the 5-position and the side chain groups on the amino alcohols at the 7-position enhanced the intracellular c-Src inhibitory activity and increased central nervous system (CNS) penetration. In the present study, 6l exhibited significant in vivo efficacy in a middle cerebral artery (MCA) occlusion model in rats.
Mukaiyama
Harunobu
H
Central Research Laboratory, Kissei Pharmaceutical Company Ltd, 4365-1, Azumino-city, Nagano 399-8304, Japan. harunobu_mukaiyama@pharm.kissei.co.jp
Nishimura
Toshihiro
T
Kobayashi
Satoko
S
Komatsu
Yoshimitsu
Y
Kikuchi
Shinji
S
Ozawa
Tomonaga
T
Kamada
Noboru
N
Ohnota
Hideki
H
D000818:Animals; D020650:Combinatorial Chemistry Techniques; D020768:Middle Cerebral Artery / Q000187:drug effects; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
D026902:Potassium Channel Blockers; D011720:Pyrazoles; D011743:Pyrimidines; D019061:src-Family Kinases