title: Preclinical pharmacology, ocular tolerability and ocular hypotensive efficacy of a novel non-peptide bradykinin mimetic small molecule.
abstract: We sought to characterize the ocular pharmacology, tolerability and intraocular pressure (IOP)-lowering efficacy of FR-190997, a non-peptidic bradykinin (BK) B2-receptor agonist. FR-190997 possessed a relatively high receptor binding affinity (Ki = 27 nM) and a high in vitro potency (EC50 = 18.3 ± 4.4 nM) for inositol-1-phosphate generation via human cloned B2-receptors expressed in host cells with mimimal activity at B1-receptors. It also mobilized intracellular Ca2+ in isolated human trabecular meshwork (h-TM), ciliary muscle (h-CM), and in immortalized non-pigmented ciliary epithelial (h-iNPE) cells (EC50s = 167-384 nM; Emax = 32-86% of BK-induced response). HOE-140, a selective B2-receptor antagonist, potently blocked the latter effects of FR-190997 (e.g., IC50 = 7.3 ± 0.6 nM in h-CM cells). FR-190997 also stimulated the release of prostaglandins (PGs) from h-TM and h-CM cells (EC50s = 60-84 nM; Emax = 29-44% relative to max. BK-induced effects). FR-190997 (0.3-300 μg t.o.) did not activate cat corneal polymodal nociceptors and did not cause ocular discomfort in Dutch-Belted rabbits, but it was not well tolerated in New Zealand albino rabbits and Hartley guinea pigs. A single topical ocular (t.o.) dose of 1% FR-190997 in Dutch-Belted rabbits and mixed breed cats did not lower IOP. However, FR-190997 efficaciously lowered IOP of conscious ocular hypertensive cynomolgus monkey eyes (e.g., 34.5 ± 7.5% decrease; 6 h post-dose of 30 μg t.o.; n = 8). Thus, FR-190997 is an unexampled efficacious ocular hypotensive B2-receptor non-peptide BK agonist that activates multiple signaling pathways to cause IOP reduction.
authors.affiliation: Alcon Research, Ltd (a Novartis Company), 6201 South Freeway, Fort Worth, TX 76134-2099, USA. Electronic address: naj.sharif@alcon.com.
authors.forename: Najam A
authors.initials: NA
authors.lastname: Sharif
authors.affiliation: Alcon Research, Ltd (a Novartis Company), 6201 South Freeway, Fort Worth, TX 76134-2099, USA.
authors.forename: Linya
authors.initials: L
authors.lastname: Li
authors.affiliation: Alcon Research, Ltd (a Novartis Company), 6201 South Freeway, Fort Worth, TX 76134-2099, USA.
authors.forename: Parvaneh
authors.initials: P
authors.lastname: Katoli
authors.affiliation: Alcon Research, Ltd (a Novartis Company), 6201 South Freeway, Fort Worth, TX 76134-2099, USA.
authors.forename: Shouxi
authors.initials: S
authors.lastname: Xu
authors.affiliation: Alcon Research, Ltd (a Novartis Company), 6201 South Freeway, Fort Worth, TX 76134-2099, USA.
authors.forename: James
authors.initials: J
authors.lastname: Veltman
authors.affiliation: Alcon Research, Ltd (a Novartis Company), 6201 South Freeway, Fort Worth, TX 76134-2099, USA.
authors.forename: Byron
authors.initials: B
authors.lastname: Li
authors.affiliation: Alcon Research, Ltd (a Novartis Company), 6201 South Freeway, Fort Worth, TX 76134-2099, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Scott
authors.affiliation: Alcon Research, Ltd (a Novartis Company), 6201 South Freeway, Fort Worth, TX 76134-2099, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Wax
authors.affiliation: Institute of Neuroscience, University Miguel Hernandez-CSIC, San Juan Campus, Alicante, Spain.
authors.forename: Juana
authors.initials: J
authors.lastname: Gallar
authors.affiliation: Institute of Neuroscience, University Miguel Hernandez-CSIC, San Juan Campus, Alicante, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Acosta
authors.affiliation: Institute of Neuroscience, University Miguel Hernandez-CSIC, San Juan Campus, Alicante, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Belmonte
mesh_terms: D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D002415:Cats; D003412:Cricetulus; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D006168:Guinea Pigs; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism; D007429:Intraocular Pressure / Q000187:drug effects*; D008252:Macaca fascicularis; D011453:Prostaglandins / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology*; D011817:Rabbits; D043782:Receptor, Bradykinin B2 / Q000819:agonists*; D015398:Signal Transduction; D014129:Trabecular Meshwork / Q000187:drug effects* / Q000378:metabolism
chemical_list: C107104:FR 190997; D007295:Inositol Phosphates; D011453:Prostaglandins; D011804:Quinolines; D043782:Receptor, Bradykinin B2; C002647:inositol 1-phosphate; D002118:Calcium
keywords: Bradykinin; FR-190997; Glaucoma; IOP; Ocular hypertension