title: Pharmacology of XR510, a potent orally active nonpeptide angiotensin II AT1 receptor antagonist with high affinity for the AT2 receptor subtype.
abstract: The angiotensin II (Ang II) type 1 receptor (AT1) mediates all known physiological effects of ANG II, whereas functions of the type 2 (AT2) receptor are not clear. Should undesirable AT2 effects be identified, it may be advantageous to combine antagonism of AT1 and AT2 receptors. XR510 was shown to inhibit the specific binding of [125I]Sar1,Ile8-Ang II for AT1 and AT2 subtype binding sites in rat adrenal membranes with IC50 of 0.26 and 0.28 nM, respectively, and in human tissues with subnanomolar binding affinity. In isolated rabbit aorta, XR510 exerted insurmountable Ang II antagonism with a Kb value of 4 nM. In conscious renal hypertensive rats, XR510 decreased blood pressure (BP) with intravenous (i.v.) and oral (p.o.) ED30 of 0.08 and 0.27 mg/kg, respectively. In spontaneously hypertensive rats (SHR), repeated daily oral dosing of XR510, losartan, and enalapril at 30 mg/kg/day decreased BP similarly. In conscious furosemide-treated dogs, XR510, given either intravenously or orally, decreased BP. These results suggest that XR510 is an orally active and selective Ang II receptor antagonist with equal binding affinities for AT1 and AT2 receptor binding sites.
authors.affiliation: DuPont Merck Pharmaceutical Company, Wilmington, Delaware 19880-0400, USA.
authors.forename: P C
authors.initials: PC
authors.lastname: Wong
authors.forename: M L
authors.initials: ML
authors.lastname: Quan
authors.forename: J M
authors.initials: JM
authors.lastname: Saye
authors.forename: R
authors.initials: R
authors.lastname: Bernard
authors.forename: E J
authors.initials: EJ
authors.lastname: Crain
authors.forename: D E
authors.initials: DE
authors.lastname: McCall
authors.forename: C A
authors.initials: CA
authors.lastname: Watson
authors.forename: A M
authors.initials: AM
authors.lastname: Zaspel
authors.forename: R D
authors.initials: RD
authors.lastname: Smith
authors.forename: R R
authors.initials: RR
authors.lastname: Wexler
mesh_terms: D015059:1-Sarcosine-8-Isoleucine Angiotensin II / Q000378:metabolism*; D000284:Administration, Oral; D000311:Adrenal Glands / Q000378:metabolism; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use; D001667:Binding, Competitive; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects; D003655:Decerebrate State; D004285:Dogs; D004656:Enalapril / Q000627:therapeutic use; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D006977:Hypertension, Renal / Q000188:drug therapy; D007093:Imidazoles / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D007275:Injections, Intravenous; D019808:Losartan; D008297:Male; D011817:Rabbits; D011869:Radioligand Assay; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley; D013777:Tetrazoles / Q000627:therapeutic use
chemical_list: D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D007093:Imidazoles; D013777:Tetrazoles; C095055:XR 510; D004656:Enalapril; D015059:1-Sarcosine-8-Isoleucine Angiotensin II; D019808:Losartan