Preclinical pharmacology, ocular tolerability and ocular hypotensive efficacy of a novel non-peptide bradykinin mimetic small molecule

We sought to characterize the ocular pharmacology, tolerability and intraocular pressure (IOP)-lowering efficacy of FR-190997, a non-peptidic bradykinin (BK) B-2-receptor agonist. FR-190997 possessed a relatively high receptor binding affinity (K-i = 27 nM) and a high in vitro potency (EC50 = 18.3 +/- 4.4 nM) for inositol-1-phosphate generation via human cloned B-2-receptors expressed in host cells with mimimal activity at B-1-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 (EC(50)s = 167-384 nM; E-max = 32-86% of BK-induced response). HOE-140, a selective B-2-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 (EC(50)s = 60-84 nM; E-max = 29-44% relative to max. BK-induced effects). FR-190997 (0.3-300 mu g 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 mu g t.o.; n = 8). Thus, FR-190997 is an unexampled efficacious ocular hypotensive B-2-receptor non-peptide BK agonist that activates multiple signaling pathways to cause IOP reduction. (C) 2014 Elsevier Ltd. All rights reserved.