{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2024,11,1]],"date-time":"2024-11-01T04:11:26Z","timestamp":1730434286925,"version":"3.28.0"},"reference-count":29,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[1999,10,1]],"date-time":"1999-10-01T00:00:00Z","timestamp":938736000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[1999,10,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>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.<\/jats:p>\n               <jats:p>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 \u03b3 10 \u03bcM 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 non-competitively 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\u201385% 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\u22121) 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\u22121). In conscious renal hypertensive rats oral administration of KR-30988 produced a dose-dependent and long-lasting (\u03b3 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\u22121, respectively). In conscious furosemide-treated dogs oral administration of KR-30988 produced a dose-dependent and long-lasting (\u03b3 8 h) hypotensive effect with a rapid onset of action (time to Emax, the maximum effect, 1-2h); KR-30988 was eight times more potent than losartan (ED20, the dose reducing mean arterial blood pressure by 20 mmHg, 1.04 and 7.96 mg kg\u22121, respectively).<\/jats:p>\n               <jats:p>These results suggest that KR-30988 is a potent, orally active selective AT1 receptor antagonist with a mode of insurmountable antagonism.<\/jats:p>","DOI":"10.1211\/0022357991776732","type":"journal-article","created":{"date-parts":[[2002,10,1]],"date-time":"2002-10-01T22:04:05Z","timestamp":1033509845000},"page":"1191-1200","source":"Crossref","is-referenced-by-count":0,"title":["Pharmacological Characterization of KR-30988, a Novel Non-peptide AT1 Receptor Antagonist, in Rat, Rabbit and Dog"],"prefix":"10.1093","volume":"51","author":[{"given":"Byung Ho","family":"Lee","sequence":"first","affiliation":[{"name":"Screening and Toxicology Research Centre, Korea Research Institute of Chemical Technology , Taejon,","place":["Republic of Korea"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sung Ho","family":"Lee","sequence":"additional","affiliation":[{"name":"Screening and Toxicology Research Centre, Korea Research Institute of Chemical Technology , Taejon,","place":["Republic of Korea"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yi Sook","family":"Jung","sequence":"additional","affiliation":[{"name":"Screening and Toxicology Research Centre, Korea Research Institute of Chemical Technology , Taejon,","place":["Republic of Korea"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ho Won","family":"Seo","sequence":"additional","affiliation":[{"name":"Screening and Toxicology Research Centre, Korea Research Institute of Chemical Technology , Taejon,","place":["Republic of Korea"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sung Eun","family":"Yoo","sequence":"additional","affiliation":[{"name":"Bio-Organic Science Division, Korea Research Institute of Chemical Technology , Taejon,","place":["Republic of Korea"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hwa Sup","family":"Shin","sequence":"additional","affiliation":[{"name":"Screening and Toxicology Research Centre, Korea Research Institute of Chemical Technology , Taejon,","place":["Republic of Korea"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[1999,10,1]]},"reference":[{"key":"2024103110045989400_cit1","first-page":"310","article-title":"Effects of antihypertensive treatment on systolic blood pressure and renin in experimental hypertension in rats","volume":"208","author":"Cangiano","year":"1979","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"2024103110045989400_cit2","doi-asserted-by":"crossref","first-page":"3099","DOI":"10.1016\/0006-2952(73)90196-2","article-title":"Relationship between the inhibition constant (Ki) and the concentration of inhibitor which causes 50 percent inhibition (IC50) of an enzyme reaction","volume":"22","author":"Cheng","year":"1973","journal-title":"Biochem. Pharmacol."},{"key":"2024103110045989400_cit3","doi-asserted-by":"crossref","first-page":"144","DOI":"10.2165\/00003495-198428020-00004","article-title":"Haemodynamic responses to specific renin-angiotensin inhibitors in hypertension and congestive heart failure","volume":"28","author":"Cody","year":"1984","journal-title":"Drugs"},{"key":"2024103110045989400_cit4","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1161\/01.CIR.91.3.691","article-title":"Losartan in heart failure: hemodynamic effects and tolerability. Losartan hemodynamic study group","volume":"91","author":"Crozier","year":"1995","journal-title":"Circulation"},{"key":"2024103110045989400_cit5","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1016\/0895-7061(95)00081-Y","article-title":"Efficacy and tolerability of losartan potassium and atenolol in patients with mild to moderate essential hypertension","volume":"8","author":"Dahlof","year":"1995","journal-title":"Am. J. Hypertens."},{"key":"2024103110045989400_cit6","first-page":"S31","article-title":"Hemodynamic and neurohumoral effects of the angiotensin II antagonist losartan in patients with heart failure","volume":"12","author":"Dickstein","year":"1994","journal-title":"J. Hypertens."},{"key":"2024103110045989400_cit7","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1007\/BF03029807","article-title":"The role of neuropeptides in cardiovascular regulation","volume":"5","author":"Ganten","year":"1991","journal-title":"Cardiovasc. Drugs. Ther."},{"key":"2024103110045989400_cit8","first-page":"78","article-title":"A method of stimulating the complete sympathetic outflow from the spinal cord to blood vessels in the pithed rat","volume":"30","author":"Gillespie","year":"1967","journal-title":"Br. J. Pharmacol."},{"key":"2024103110045989400_cit9","doi-asserted-by":"crossref","first-page":"1431","DOI":"10.1056\/NEJM199405193302008","article-title":"The emerging concept of vascular remodeling","volume":"330","author":"Gobbons","year":"1994","journal-title":"N. Engl. J. Med."},{"key":"2024103110045989400_cit10","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1016\/S1054-3589(08)60498-6","article-title":"Angiotensin II receptor pharmacology","volume":"28","author":"Griendling","year":"1994","journal-title":"Adv. Pharmacol."},{"key":"2024103110045989400_cit11","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1007\/BF02980458","article-title":"In vivo pharmacological evaluation of newly synthesized non-peptidic AT1 receptor antagonists in rats","volume":"17","author":"Lee","year":"1994","journal-title":"Arch. Pharm. Res."},{"key":"2024103110045989400_cit12","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1097\/00005344-199801000-00013","article-title":"Hemodynamic profile of SKP-450, a new potassium-channel activator","volume":"31","author":"Lee","year":"1998","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"2024103110045989400_cit13","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1097\/00005344-198811000-00006","article-title":"Cromakalim, a potassium channel activator: a comparison of its cardiovascular haemodynamic profile and tissue specificity with those of pinacidil and nicorandil","volume":"12","author":"Longman","year":"1988","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"2024103110045989400_cit14","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/S0014-2999(96)00837-0","article-title":"Candesartan (CV-11974) dissociates slowly from the angiotensin AT1 receptor","volume":"319","author":"Ojima","year":"1997","journal-title":"Eur. J. Pharmacol."},{"key":"2024103110045989400_cit15","first-page":"753","article-title":"Functional studies but not receptor binding can distinguish surmountable from insurmountable AT1 antagonism","volume":"273","author":"Panek","year":"1995","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"2024103110045989400_cit16","first-page":"189","article-title":"pA2, a new scale for the measurement of drug antagonism","volume":"2","author":"Schild","year":"1947","journal-title":"Br. J. Pharmacol."},{"key":"2024103110045989400_cit17","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1159\/000028188","article-title":"Cardiovascular pharmacology of SKP-450, a new potassium channel activator, and its major metabolites SKP-818 and SKP-310","volume":"56","author":"Shin","year":"1998","journal-title":"Pharmacology"},{"key":"2024103110045989400_cit18","first-page":"1","article-title":"Losartan potassium (Cozaar): a non-peptide antagonist of angiotensin II","volume":"32","author":"Smith","year":"1996","journal-title":"Drugs Today"},{"key":"2024103110045989400_cit19","doi-asserted-by":"crossref","first-page":"296","DOI":"10.2165\/00003495-198733040-00002","article-title":"Nicardipine: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy, in the treatment of angina pectoris, hypertension and related cardiovascular disorders","volume":"33","author":"Sorkin","year":"1987","journal-title":"Drugs"},{"key":"2024103110045989400_cit20","first-page":"205","article-title":"Angiotensin II receptors and angiotensin II receptor antagonists","volume":"45","author":"Timmermans","year":"1993","journal-title":"Pharmacol. Rev."},{"key":"2024103110045989400_cit21","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/0165-6147(87)90013-7","article-title":"The renin-angiotensin system","volume":"8","author":"Vallotton","year":"1987","journal-title":"Trends Pharmacol. Sci."},{"key":"2024103110045989400_cit22","first-page":"1081","article-title":"Different types of receptor interaction of peptide and non-peptide angiotensin II antagonists revealed by receptor binding and functional studies","volume":"41","author":"Wienen","year":"1992","journal-title":"Mol. Pharmacol."},{"key":"2024103110045989400_cit23","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1111\/j.1476-5381.1993.tb13800.x","article-title":"Pharmacological characterization of the novel non-peptide angiotensin II receptor antagonist, BIBR 277","volume":"110","author":"Wienen","year":"1993","journal-title":"Br. J. Pharmacol."},{"key":"2024103110045989400_cit24","first-page":"49","article-title":"Nonpeptide angiotensin II receptor antagonists: insurmountable angiotensin II antagonism of EXP3892 is reversed by the surmountable antagonist DuP753","volume":"258","author":"Wong","year":"1991","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"2024103110045989400_cit25","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1161\/01.HYP.15.5.459","article-title":"Hypotensive action of DuP 753, an angiotensin II antagonist, in spontaneously hypertensive rats","volume":"15","author":"Wong","year":"1990","journal-title":"Hypertension"},{"key":"2024103110045989400_cit26","first-page":"211","article-title":"Non-peptide angiotensin II receptor antagonists. XI. Pharmacology of EXP3174: an active metabolite of DuP 753, an orally active antihypertensive agent","volume":"255","author":"Wong","year":"1990","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"2024103110045989400_cit27","doi-asserted-by":"crossref","first-page":"288S","DOI":"10.1093\/ajh\/4.4.288S","article-title":"In vivo pharmacology of DuP 753","volume":"4","author":"Wong","year":"1991","journal-title":"Am. J. Hypertens."},{"key":"2024103110045989400_cit28","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1016\/0014-2999(91)90274-T","article-title":"Non-peptide angiotensin II receptor antagonists: studies with DuP 753 and EXP3174 in dogs","volume":"202","author":"Wong","year":"1991","journal-title":"Eur. J. Pharmacol."},{"issue":"Suppl","key":"2024103110045989400_cit29","first-page":"S132","article-title":"The angiotensin receptor antagonist, irbesartan, reduces renal injury in experimental chronic renal failure","volume":"57","author":"Ziai","year":"1996","journal-title":"Kidney Int."}],"container-title":["Journal of Pharmacy and Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1211%2F0022357991776732","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/jpp\/article-pdf\/51\/10\/1191\/60263063\/0022357991776732.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jpp\/article-pdf\/51\/10\/1191\/60263063\/0022357991776732.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,31]],"date-time":"2024-10-31T10:40:08Z","timestamp":1730371208000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jpp\/article\/51\/10\/1191\/6157310"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1999,10,1]]},"references-count":29,"journal-issue":{"issue":"10","published-online":{"date-parts":[[1999,10,1]]},"published-print":{"date-parts":[[1999,10,1]]}},"URL":"https:\/\/doi.org\/10.1211\/0022357991776732","relation":{},"ISSN":["0022-3573","2042-7158"],"issn-type":[{"type":"print","value":"0022-3573"},{"type":"electronic","value":"2042-7158"}],"subject":[],"published-other":{"date-parts":[[1999,10]]},"published":{"date-parts":[[1999,10,1]]}}}