Synthesis and Angiotensin II Receptor Antagonist Activity of C-Linked Pyrazole Derivatives

• Published in: Chemical & pharmaceutical bulletin Vol. 42; no. 8; pp. 1617 - 1630
• Main Authors: NICOLAI, Eric, CURE, Gerard, GOYARD, Joel, KIRCHNER, Maud, TEULON, Jean-Marie, VERSIGNY, Annie, CAZES, Michele, VIRONE-ODDOS, Angela, CAUSSADE, Francois, CLOAREC, Alix
• Format: Journal Article
• Language: English
• Published: TOKYO The Pharmaceutical Society of Japan 1994; Pharmaceutical Soc Japan; Maruzen; Japan Science and Technology Agency
• Subjects: 2'-(1H-tetrazol-5-yl)biphenyl; angiotensin II; angiotensin II receptor antagonist; Angiotensin Receptor Antagonists; Animals; antihypertensive; Antihypertensive agents; Antihypertensive Agents - chemical synthesis; Antihypertensive Agents - pharmacology; Antihypertensive Agents - therapeutic use; Biological and medical sciences; Biphenyl Compounds - pharmacology; Biphenyl Compounds - therapeutic use; Blood Pressure - drug effects; Cardiovascular system; Chemistry; Chemistry, Medicinal; Chemistry, Multidisciplinary; Hypertension, Renal - drug therapy; Imidazoles - pharmacology; Imidazoles - therapeutic use; Life Sciences & Biomedicine; Losartan; Magnetic Resonance Spectroscopy; Medical sciences; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Physical Sciences; pyrazole; Pyrazoles - chemical synthesis; Pyrazoles - chemistry; Pyrazoles - pharmacology; Pyrazoles - therapeutic use; Rats; Science & Technology; structure-activity relationship; Tetrazoles - chemistry; Tetrazoles - pharmacology; Tetrazoles - therapeutic use; SYSTEM; ACID; RENIN; STRUCTURE-ACTIVITY RELATIONSHIP; ANGIOTENSIN II RECEPTOR ANTAGONIST; SPONTANEOUSLY HYPERTENSIVE RATS; PRESSURE; PYRAZOLE; POTENT; INHIBITION; PHARMACOLOGY; DUP-753; ANTIHYPERTENSIVE; 2'-(1H-TETRAZOL-5-YL)BIPHENYL; ANGIOTENSIN II; Hypertension; Tetrazole derivatives; Rat; Rodentia; Oral administration; Cardiovascular disease; In vitro; In vivo; Vertebrata; Chemotherapy; Experimental disease; Mammalia; Treatment; Structure activity relation; Biphenyl derivatives; Nonpeptide compound; Animal; Pyrazole derivatives; Peptidergic receptor; Antihypertensive agent; Angiotensin antagonist; Angiotensin II; Chemical synthesis
• ISSN: 0009-2363; 1347-5223
• DOI: 10.1248/cpb.42.1617

The synthesis and pharmacological activity of new nonpeptide angiotensin II (AII) receptor antagonists are presented. These 5-O-substituted and 5-C-substituted 3-alkylpyrazole derivatives represent a new series of antagonists and have led to to the discovery of compounds with potent oral antihypertensive activity in a renal artery-ligated rat model. In vitro, they displayed a high affinity for rat adrenal AII receptors. In vivo structure-activity relationship study has shown the importance of the 4-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl moiety for oral activity and the critical role of alkyl substituents at the 1- or 2-position. In the case of oral administration, 5-C derivatives were found to be, on the whole, more potent than 5-O derivatives. UP 221-78, 5-hydroxymethyl-3-n-propyl-1-(2, 2, 2-trifluoroethyl)-4-[[2'-(1H-tetrazol-5-yl)biphenyl-4-]methyl]-1H-pyrazole (79), displayed equivalent antihypertensive activity to the well known antagonist Losartan at 3 mg/kg p.o. in renal artery-ligated rats, with maximal decreases in mean arterial pressure of 60 and 63 mmHg for Losartan and UP 221-78, respectively.