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

Najam A. Sharif, Linya Li, Parvaneh Katoli, Shouxi Xu, James Veltman, Byron Li, Daniel Scott, Martin Wax, Juana Gallar, Carmen Acosta, Carlos Belmonte

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2 Scopus citations

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=27nM) and a high invitro potency (EC50=18.3±4.4nM) 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=167-384nM; 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±0.6nM in h-CM cells). FR-190997 also stimulated the release of prostaglandins (PGs) from h-TM and h-CM cells (EC50s=60-84nM; Emax=29-44% relative to max. BK-induced effects). FR-190997 (0.3-300μg 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; 6h post-dose of 30μg 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.

Original languageEnglish (US)
Pages (from-to)170-180
Number of pages11
JournalExperimental Eye Research
Volume128
DOIs
StatePublished - Nov 1 2014

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Keywords

  • Bradykinin
  • FR-190997
  • Glaucoma
  • IOP
  • Ocular hypertension

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

Cite this

Sharif, N. A., Li, L., Katoli, P., Xu, S., Veltman, J., Li, B., Scott, D., Wax, M., Gallar, J., Acosta, C., & Belmonte, C. (2014). Preclinical pharmacology, ocular tolerability and ocular hypotensive efficacy of a novel non-peptide bradykinin mimetic small molecule. Experimental Eye Research, 128, 170-180. https://doi.org/10.1016/j.exer.2014.10.008