title: FR-190997, a nonpeptide bradykinin B2-receptor partial agonist, is a potent and efficacious intraocular pressure lowering agent in ocular hypertensive cynomolgus monkeys.
abstract: Preclinical Research FR-190997 (8-[2,6-dichloro-3-[N-[(E)-4-(N-methylcarbamoyl) cinnaminoacetyl]-N-methylamino]benzyloxy]-2-methyl-4- (2-pyridylmethoxy) quinoline), a nonpeptide bradykinin (BK) B2-receptor-selective agonist, represents a novel class of ocular hypotensive agents. FR-190997 exhibited a high affinity for the human cloned B2-receptor (Ki = 9.8 nM) and a relatively high potency (EC50 = 155 nM) for mobilizing intracellular Ca(2+) ([Ca(2+)]i) in human ocular cells from nonpigmented ciliary epithelium; trabecular meshwork [h-TM]; ciliary muscle [h-CM] that are involved in regulating intraocular pressure (IOP). Unlike BK, FR-190997 behaved as a partial agonist (Emax = 38-80%) in these cells and its [Ca(2+)]i-mobilizing effects were blocked by the B2-receptor-selective antagonists (HOE-140, Ki = 0.8-7 nM; WIN-64338, Ki = 157-425 nM). FR-190997 stimulated the production of prostaglandins (PGs) in h-CM and h-TM cells (EC50 = 15-19 nM; Emax = 27-33%); an effect that was reduced by the cyclooxygenase-2 inhibitor bromfenac, and by HOE-140. FR-190997 also induced pro-matrix metalloproteinase (MMP)-1 and MMP-3 release from h-CM cells. FR-190997 significantly lowered IOP (37% [P < 0.001] with 30 μg, 24 h post-topical ocular dosing) in ocular hypertensive eyes of conscious Cynomolgus monkeys. This effect was reduced by bromfenac and completely blocked by a B2-antagonist. FR-190997 primarily stimulated uveoslceral outflow (UVSO) of aqueous humor (2.6 to 3.9-fold above baseline). In conclusion, FR-190997 is a B2-receptor selective partial agonist that activates phospholipase C, mobilizes [Ca(2+)]; induces PG and pro-MMP production, and that profoundly lowers IOP by promoting UVSO in ocular hypertensive Cynomolgus monkey eyes.
authors.affiliation: Pharmaceutical Research, Alcon Research, Ltd (A Novartis Company), Fort Worth, TX, USA.
authors.forename: Najam A
authors.initials: NA
authors.lastname: Sharif
authors.forename: Parvaneh
authors.initials: P
authors.lastname: Katoli
authors.forename: Daniel
authors.initials: D
authors.lastname: Scott
authors.forename: Linya
authors.initials: L
authors.lastname: Li
authors.forename: Curtis
authors.initials: C
authors.lastname: Kelly
authors.forename: Shouxi
authors.initials: S
authors.lastname: Xu
authors.forename: Shahid
authors.initials: S
authors.lastname: Husain
authors.forename: Carol
authors.initials: C
authors.lastname: Toris
authors.forename: Craig
authors.initials: C
authors.lastname: Crosson
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D001577:Benzophenones / Q000494:pharmacology; D001969:Bromobenzenes / Q000494:pharmacology; D016466:CHO Cells; D002478:Cells, Cultured; D003412:Cricetulus; D004195:Disease Models, Animal; D005123:Eye / Q000187:drug effects* / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008252:Macaca fascicularis; D009798:Ocular Hypertension / Q000188:drug therapy*; D011804:Quinolines / Q000008:administration & dosage* / Q000627:therapeutic use*; D043782:Receptor, Bradykinin B2 / Q000819:agonists*; D013552:Swine
chemical_list: D000959:Antihypertensive Agents; D001577:Benzophenones; D001969:Bromobenzenes; C107104:FR 190997; D011804:Quinolines; D043782:Receptor, Bradykinin B2; C053083:bromfenac
keywords: FR-190997; bradykinin; intraocular pressure