title: Synthesis and structure-activity relationship of a new series of potent angiotensin II receptor antagonists: pyrazolo[1,5-a]pyrimidine derivatives.
abstract: We have already reported 7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid derivatives, which are potent in vitro angiotensin II (AII) antagonists, but have no oral antihypertensive activity. Removal of the carboxylic acid and replacement of the heteroaromatic system afforded potent in vitro antagonists. Removal of the carbonyl oxygen and changing the position of the biphenyltetrazole substituent were critical to the display of oral activity. To improve the in vitro and oral activities, modifications were made of the substituents at the 3- and 5-positions of the pyrazolo[1,5-a]pyrimidine. Structure-activity studies showed the methyl substituent at the 3-position to be essential for potent in vivo activity. We present the design, syntheses, and biological data of a series of pyrazolo[1,5-a]pyrimidine derivatives, which are orally active AII receptor antagonists.
authors.affiliation: Shionogi Research Laboratories, Shionogi & Co., Ltd., Osaka, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Shiota
authors.forename: T
authors.initials: T
authors.lastname: Yamamori
authors.forename: K
authors.initials: K
authors.lastname: Sakai
authors.forename: M
authors.initials: M
authors.lastname: Kiyokawa
authors.forename: T
authors.initials: T
authors.lastname: Honma
authors.forename: M
authors.initials: M
authors.lastname: Ogawa
authors.forename: K
authors.initials: K
authors.lastname: Hayashi
authors.forename: N
authors.initials: N
authors.lastname: Ishizuka
authors.forename: K
authors.initials: K
authors.lastname: Matsumura
authors.forename: M
authors.initials: M
authors.lastname: Hara
authors.forename: M
authors.initials: M
authors.lastname: Fujimoto
authors.forename: T
authors.initials: T
authors.lastname: Kawabata
authors.forename: S
authors.initials: S
authors.lastname: Nakajima
mesh_terms: D000804:Angiotensin II / Q000378:metabolism*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis / Q000494:pharmacology; D001667:Binding, Competitive; D019556:COS Cells; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism; D008566:Membranes / Q000378:metabolism; D008958:Models, Molecular; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D013329:Structure-Activity Relationship
chemical_list: D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D011743:Pyrimidines; D000804:Angiotensin II