title: Pharmacological profile of TH-142177, a novel orally active AT1-receptor antagonist.
abstract: The pharmacological properties of TH-142177 (N-n-butyl-N-[2'-(1-H-tetrazole-5-yl) biphenyl-4-yl]-methyl-(N-carboxymethyl-benzylamino)-acetamide), a novel antagonist of the angiotensin II (AII) AT1 receptor, were studied in vitro and in vivo, and compared to those of losartan. In the rat isolated aorta, TH-142177 produced parallel shifts to the right of the concentration-response curves for AII-induced contractions without affecting the maximal response (pA2 = 9.07). The inhibitory potency of TH-142177 in the aorta was about three times greater than that of losartan. TH-142177 completely inhibited the specific binding of [125I]AII to AT1 receptor in rat aortic membranes (Ki = 1.6 x 10(-8) M), whereas specific [125I]AII binding to AT2 receptor in bovine cerebellum and human myocardium was not affected by concentrations of TH-142177 up to 10(-5) M. Losartan also inhibited the [125I]AII binding to rat aortic membranes (Ki = 2.2 x 10(-8) M). Following the intravenous administration to anesthetized normotensive rats, TH-142177 dose-dependently inhibited the increase in systolic blood pressure induced by an intravenous bolus injection of AII that was 1.5 times less potent than losartan. Furthermore, the oral administration of TH-142177 to conscious renal hypertensive rats exerted a dose-dependent reduction of systolic blood pressure without significantly effecting the heart rate. TH-142177 was at least three times more potent than losartan. These results demonstrate that TH-142177 is a potent and selective antagonist of AT1 receptors and by oral administration has a long-lasting antihypertensive activity.
authors.affiliation: Pharmacology Research Laboratory, Taiho Pharmaceutical Co. Ltd., Ebisuno, Tokushima, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Nozawa
authors.forename: A
authors.initials: A
authors.lastname: Haruno
authors.forename: N
authors.initials: N
authors.lastname: Oda
authors.forename: Y
authors.initials: Y
authors.lastname: Yamasaki
authors.forename: N
authors.initials: N
authors.lastname: Matsuura
authors.forename: H
authors.initials: H
authors.lastname: Miyake
authors.forename: S
authors.initials: S
authors.lastname: Yamada
authors.forename: R
authors.initials: R
authors.lastname: Kimura
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001011:Aorta / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects*; D002417:Cattle; D002531:Cerebellum / Q000378:metabolism; D005998:Glycine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D006977:Hypertension, Renal / Q000188:drug therapy; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D009206:Myocardium / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000378:metabolism; D013777:Tetrazoles / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D057911:Angiotensin Receptor Antagonists; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; C109125:TH 142177; D013777:Tetrazoles; D000804:Angiotensin II; D005998:Glycine