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Synthesis and Structure-Activity Relationship of a New Series of Potent Angiotensin II Receptor Antagonists: Pyrazolo(1,5-a)pyrimidine Derivatives.

1999; Pharmaceutical Society of Japan; Volume: 47; Issue: 7 Linguagem: Inglês

10.1248/cpb.47.928

1347-5223

Takeshi Shiota, Tohru Yamamori, K. Sakai, Machiko Kiyokawa, Teruki Honma, Masayoshi Ogawa, Kyohei Hayashi, N Ishizuka, Kenta Matsumura, Mariko Hara, Masafumi Fujimoto, Tomoji Kawabata, Satoru Nakajima,

Synthesis and biological activity

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.