title: In vitro pharmacology of a nonpeptidic angiotensin II receptor antagonist, SC-51316.
abstract: The properties of a novel nonpeptidic angiotensin II (AII) receptor antagonist, 2,5-dibutyl-2,4-dihydro-4-([2-(1H-tetrazol-5-yl)(1,1'-biphenyl) -4'-yl]methyl)-3H-1,2,4-triazol-3-one (SC-51316), are described. SC-51316 inhibited [125I]AII binding selectively to the AT1 receptor with IC50 values of 3.6 and 5.1 nM in rat adrenal cortical and rat uterine membrane preparations, respectively. The compound was a competitive and reversible antagonist of AII-mediated contraction of rabbit aortic rings with a pA2 of 8.86. In addition, SC-51316 inhibited AII-induced aldosterone release from rat adrenal zona glomerulosa cells and blocked inhibition of renin release by AII from rat kidney slices with pA2 values of 8.62 and 8.9, respectively. The agent (0.1 mM) did not inhibit angiotensin-converting enzyme or plasma renin activity. These data demonstrate that SC-51316 is a potent AII receptor antagonist which may prove to be useful as a pharmacologic tool for studying the role of the renin-angiotensin system in cardiovascular diseases.
authors.affiliation: Department of Cardiovascular Diseases Research, G. D. Searle & Co., St. Louis, Missouri.
authors.forename: G M
authors.initials: GM
authors.lastname: Olins
authors.forename: V M
authors.initials: VM
authors.lastname: Corpus
authors.forename: E G
authors.initials: EG
authors.lastname: McMahon
authors.forename: M A
authors.initials: MA
authors.lastname: Palomo
authors.forename: J R
authors.initials: JR
authors.lastname: Schuh
authors.forename: D J
authors.initials: DJ
authors.lastname: Blehm
authors.forename: H C
authors.initials: HC
authors.lastname: Huang
authors.forename: D B
authors.initials: DB
authors.lastname: Reitz
authors.forename: R E
authors.initials: RE
authors.lastname: Manning
authors.forename: E H
authors.initials: EH
authors.lastname: Blaine
mesh_terms: D000302:Adrenal Cortex / Q000187:drug effects / Q000378:metabolism; D000450:Aldosterone / Q000378:metabolism; D000804:Angiotensin II / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D002462:Cell Membrane / Q000187:drug effects; D005260:Female; D007093:Imidazoles / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D019808:Losartan; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011945:Receptors, Angiotensin / Q000187:drug effects* / Q000378:metabolism; D012083:Renin / Q000097:blood; D013777:Tetrazoles / Q000494:pharmacology*; D014230:Triazoles / Q000494:pharmacology*; D014599:Uterus / Q000187:drug effects
chemical_list: D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D007093:Imidazoles; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D014230:Triazoles; D000804:Angiotensin II; C075064:SC 51316; D000450:Aldosterone; D012083:Renin; D019808:Losartan