title: Novel pyrazolo[1,5-a]pyrimidines as c-Src kinase inhibitors that reduce IKr channel blockade.
abstract: 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.
authors.affiliation: Central Research Laboratory, Kissei Pharmaceutical Company Ltd, 4365-1, Azumino-city, Nagano 399-8304, Japan. harunobu_mukaiyama@pharm.kissei.co.jp
authors.forename: Harunobu
authors.initials: H
authors.lastname: Mukaiyama
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Nishimura
authors.forename: Satoko
authors.initials: S
authors.lastname: Kobayashi
authors.forename: Yoshimitsu
authors.initials: Y
authors.lastname: Komatsu
authors.forename: Shinji
authors.initials: S
authors.lastname: Kikuchi
authors.forename: Tomonaga
authors.initials: T
authors.lastname: Ozawa
authors.forename: Noboru
authors.initials: N
authors.lastname: Kamada
authors.forename: Hideki
authors.initials: H
authors.lastname: Ohnota
mesh_terms: 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*
chemical_list: D026902:Potassium Channel Blockers; D011720:Pyrazoles; D011743:Pyrimidines; D019061:src-Family Kinases