Pharmacologic profiles of CA0113, a novel quinoline derivative angiotensinII AT(1)-receptor antagonist

GA0113 is a newly developed angiotensin II (Ang II) AT(1)-receptor antagoni st having a quinoline moiety. This study was undertaken to clarify the phar macologic profile of GA0113. In vitro profiles of GA0113 for Ang II recepto rs were examined in a receptor-binding assay and an Ang II-induced vasocons triction study. Antihypertensive effects after single or repeated oral admi nistrations were examined in conscious renal hypertensive (RH) or spontaneo us hypertensive (SH) rats. Blood pressure (BP) and heart rate were measured by the tail-cuff method. GA0113 interacted with AT, receptors in a competi tive manner, but showed an insurmountable antagonistic action in Ang II-ind uced vasoconstriction. In RH rats, GA0113 (0.01-1 mg/kg) reduced BP with ED 25 values of 0.015 mg/kg, and required 0.1 mg/kg for 24-h BP control. Repea ted administration of GA0113 in SH rats (0.03-0.1 mg/kg) showed moderate on set and gradually potentiated reduction of BP, which reached a plateau afte r day 4 of treatment without alteration in heart rate. There was no toleran ce of the hypotensive action or rebound phenomenon after cessation of the t reatment. In pharmacokinetic studies, GA0113 shows excellent oral bioavaila bility (94%) and a long circulating half-life (12 h) in rats. These finding s indicate that GA0113 may serve as a highly potent and effective antihyper tensive agent in humans. GA0113. with its unique chemical structure and pha rmacologic and pharmacokinetic profiles may provide new possibilities in hy pertension therapy.