Synthesis and evaluation of novel pyrazolo[1,5-alpha]pyrimidine derivatives as nonpeptide angiotensin II receptor antagonists.
A novel series of 6-alkyl-7-oxo-4,7-dihydropyrazolo[1,5-alpha]pyrimidine-3-carboxyli c acid derivatives was prepared as angiotensin II (AII) receptor antagonists. When evaluated in an in vitro binding assay using COS cells transfected with a cDNA encoding a human AT1 angiotensin II receptor, the compounds in this series showed Ki values in the range of 0.4-4.0 nM. In anesthetized spontaneously hypertensive rats (SHRs), administration of the 6-propyl derivative 4d (1 mg/kg, i.v.) reduced the mean blood pressure (MBP) by a maximum of more than 30 mmHg from the normal value.
Kiyama
R
R
Shionogi Research Laboratories, Shionogi & Co., Ltd., Osaka, Japan.
Hayashi
K
K
Hara
M
M
Fujimoto
M
M
Kawabata
T
T
Kawakami
M
M
Nakajima
S
S
Fujishita
T
T
D000804:Angiotensin II / Q000378:metabolism*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002460:Cell Line; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D011945:Receptors, Angiotensin / Q000096:biosynthesis
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D011720:Pyrazoles; D011743:Pyrimidines; D011945:Receptors, Angiotensin; D000804:Angiotensin II