title: Pharmacological characterization of KR-30988, a novel non-peptide AT1 receptor antagonist, in rat, rabbit and dog.
abstract: The pharmacological profile of KR-30988, a non-peptide AT1-selective angiotensin receptor antagonist, has been investigated by use of a variety of experimental models in-vitro and in-vivo. KR-30988 inhibited the specific binding of [125I][Sar1, Ile8]-angiotensin II to the recombinant AT1 receptor from man with a potency similar to that of losartan (IC50 values, the concentrations of drugs displacing 50% of specific binding, 13.6 and 12.3 nM, respectively), but did not inhibit the binding of [125I]CGP 42112A to recombinant AT2 receptor from man (IC50 >10 microM for both drugs). Scatchard analysis showed that KR-30988 interacted competitively with recombinant AT1 receptor from man in the same manner as losartan. In functional studies with rat and rabbit aorta, KR-30988 noncompetitively inhibited the contractile response to angiotensin II (pD2, = -log EC50 (where EC50 is the dose resulting in 50% of a reference contraction), 8.64 and 7.73, respectively) with a 20-85% decrease in the maximum contractile responses, unlike losartan. In pithed rats intravenous KR-30988 resulted in a non-parallel shift to the right of the dose-pressor response curve to angiotensin II (ID50 value, the dose inhibiting the pressor response to angiotensin II by 50%, 0.09 mg kg(-1)) with a dose-dependent reduction in the maximum responses; in this antagonistic effect KR-30988 was 20 times (approx.) more potent than losartan (ID50 1-74 mg kg(-1)). In conscious renal hypertensive rats oral administration of KR-30988 produced a dose-dependent and long-lasting (>24 h) anti-hypertensive effect; the potency was six times that of losartan (ED30 values, the dose reducing mean arterial blood pressure by 30 mmHg, 0.48 and 2.97 mg kg(-1), respectively). In conscious furosemide-treated dogs oral administration of KR-30988 produced a dose-dependent and long-lasting (>8 h) hypotensive effect with a rapid onset of action (time to Emax, the maximum effect, 1-2 h); KR-30988 was eight times more potent than losartan (ED20, the dose reducing mean arterial blood pressure by 20 mm Hg, 1.04 and 7.96 mg kg(-1), respectively). These results suggest that KR-30988 is a potent, orally active selective AT1 receptor antagonist with a mode of insurmountable antagonism.
authors.affiliation: Screening and Toxicology Research Centre, Korea Research Institute of Chemical Technology, Taejon, Republic of Korea.
authors.forename: B H
authors.initials: BH
authors.lastname: Lee
authors.forename: S H
authors.initials: SH
authors.lastname: Lee
authors.forename: Y S
authors.initials: YS
authors.lastname: Jung
authors.forename: H W
authors.initials: HW
authors.lastname: Seo
authors.forename: S E
authors.initials: SE
authors.lastname: Yoo
authors.forename: H S
authors.initials: HS
authors.lastname: Shin
mesh_terms: D000803:Angiotensin I / Q000037:antagonists & inhibitors / Q000378:metabolism; D000804:Angiotensin II / Q000037:antagonists & inhibitors* / Q000378:metabolism; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D001011:Aorta; D004285:Dogs; D005665:Furosemide; D006977:Hypertension, Renal / Q000188:drug therapy; D007093:Imidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D019808:Losartan / Q000494:pharmacology; D008297:Male; D009842:Oligopeptides / Q000494:pharmacology; D011311:Pressoreceptors / Q000187:drug effects; D011817:Rabbits; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000235:genetics; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013777:Tetrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D007093:Imidazoles; C402932:KR 30988; D009842:Oligopeptides; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D011994:Recombinant Proteins; D013777:Tetrazoles; D000804:Angiotensin II; C060894:CGP 42112A; D005665:Furosemide; D000803:Angiotensin I; D019808:Losartan