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Synthesis and Structure−Activity Relationship of a New Series of Potent AT1 Selective Angiotensin II Receptor Antagonists: 5-(Biphenyl-4-ylmethyl)pyrazoles

Almansa, Carmen ; Gómez, Luis A ; Cavalcanti, Fernando L ; de Arriba, Alberto F ; García-Rafanell, Julián ; Forn, Javier

Journal of medicinal chemistry, 1997-02, Vol.40 (4), p.547-558 [Periódico revisado por pares]

Washington, DC: American Chemical Society

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Título:
Synthesis and Structure−Activity Relationship of a New Series of Potent AT1 Selective Angiotensin II Receptor Antagonists: 5-(Biphenyl-4-ylmethyl)pyrazoles
Autor: Almansa, Carmen ; Gómez, Luis A ; Cavalcanti, Fernando L ; de Arriba, Alberto F ; García-Rafanell, Julián ; Forn, Javier
Assuntos: Angiotensin I - metabolism ; Angiotensin Receptor Antagonists ; Animals ; Antihypertensive agents ; Antihypertensive Agents - chemical synthesis ; Antihypertensive Agents - chemistry ; Antihypertensive Agents - pharmacology ; Biological and medical sciences ; Blood Pressure - drug effects ; Cardiovascular system ; Medical sciences ; Pharmacology. Drug treatments ; Pyrazoles - chemical synthesis ; Pyrazoles - chemistry ; Pyrazoles - pharmacology ; Rats ; Structure-Activity Relationship ; Tetrazoles - chemical synthesis ; Tetrazoles - chemistry ; Tetrazoles - pharmacology
É parte de: Journal of medicinal chemistry, 1997-02, Vol.40 (4), p.547-558
Notas: istex:5D1ACFCC3565C53DCD6325100005217D98CCDB56
ark:/67375/TPS-7P151236-K
Abstract published in Advance ACS Abstracts, January 1, 1997.
ObjectType-Article-1
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Descrição: The synthesis and pharmacological activity of a new series of 5-(biphenyl-4-ylmethyl)pyrazoles as potent angiotensin II antagonists both in vitro (binding of [3H]AII) and in vivo (iv, inhibition of AII-induced increase in blood pressure, pithed rats; po, furosemide-treated sodium-depleted rats) are reported. The various substituents of the pyrazole ring have been modified taking into account the receptor's requirements derived from related structure−activity relationship studies. A propyl or butyl group at position 1 as well as a carboxylic acid group at position 4 were shown to be essential for high affinity. Different groups at position 3 (H, small alkyl, phenyl, benzyl) provided good binding affinity, but oral activity was highly discriminating: bulky alkyl groups provided the highest potencies. Among the acidic isosteres tested in the biphenyl moiety, the tetrazole group proved to be the best. Compound 14n (3-tert-butyl-1-propyl-5-[[2‘-(1H-tetrazol-5-yl)-1,1‘-biphenyl-4-yl]methyl]-1H-pyrazole-4-carboxylic acid, UR-7280) shows high potency both in vitro (IC50 = 3 nM) and in vivo (iv, 61.2 ± 10% decrease in blood pressure at 0.3 mg/kg; po, 30 mmHg fall in blood pressure at 0.3 mg/kg), in comparison to losartan (IC50 = 59 nM; iv, 62.5 ± 8.9% decrease in blood pressure at 1 mg/kg; po, 13 mmHg fall in blood pressure at 3 mg/kg). These data, together with the good pharmacokinetic profile of 14n in different species, have led to its selection for clinical evaluation as an antihypertensive agent.
Editor: Washington, DC: American Chemical Society
Idioma: Inglês

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Synthesis and Structure−Activity Relationship of a New Series of Potent AT1 Selective Angiotensin II Receptor Antagonists: 5-(Biphenyl-4-ylmethyl)pyrazoles

Almansa, Carmen ; Gómez, Luis A ; Cavalcanti, Fernando L ; de Arriba, Alberto F ; García-Rafanell, Julián ; Forn, Javier

Washington, DC: American Chemical Society

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