FR-190997, a nonpeptide bradykinin B2-receptor partial agonist, is a potent and efficacious intraocular pressure lowering agent in ocular hypertensive cynomolgus monkeys

Najam A. Sharif, Parvaneh Katoli, Daniel Scott, Linya Li, Curtis Kelly, Shouxi Xu, Shahid Husain, Carol B Toris, Craig Crosson

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

FR-190997 (8-[2,6-dichloro-3-[N-[(E)-4-(N-methylcarbamoyl) cinnaminoacetyl]-Nmethylamino] 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 (K i = 9.8 nM) and a relatively high potency (EC50 = 155 nM) for mobilizing intracellular Ca2+ ([Ca2+]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 (E max = 38-80%) in these cells and its [Ca2+]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 posttopical 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 [Ca2+]; induces PG and pro-MMP production, and that profoundly lowers IOP by promoting UVSO in ocular hypertensive Cynomolgus monkey eyes.

Original languageEnglish (US)
Pages (from-to)211-223
Number of pages13
JournalDrug Development Research
Volume75
Issue number4
DOIs
StatePublished - Jan 1 2014

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Bradykinin B2 Receptors
Macaca fascicularis
Intraocular Pressure
Prostaglandins
Trabecular Meshwork
Matrix Metalloproteinase 3
Matrix Metalloproteinase 1
FR 190997
Aqueous Humor
Cyclooxygenase 2 Inhibitors
Type C Phospholipases
Bradykinin
Matrix Metalloproteinases
Epithelium
Muscles

Keywords

  • Bradykinin
  • FR-190997
  • Intraocular pressure

ASJC Scopus subject areas

  • Drug Discovery

Cite this

FR-190997, a nonpeptide bradykinin B2-receptor partial agonist, is a potent and efficacious intraocular pressure lowering agent in ocular hypertensive cynomolgus monkeys. / Sharif, Najam A.; Katoli, Parvaneh; Scott, Daniel; Li, Linya; Kelly, Curtis; Xu, Shouxi; Husain, Shahid; Toris, Carol B; Crosson, Craig.

In: Drug Development Research, Vol. 75, No. 4, 01.01.2014, p. 211-223.

Research output: Contribution to journalArticle

Sharif, Najam A. ; Katoli, Parvaneh ; Scott, Daniel ; Li, Linya ; Kelly, Curtis ; Xu, Shouxi ; Husain, Shahid ; Toris, Carol B ; Crosson, Craig. / FR-190997, a nonpeptide bradykinin B2-receptor partial agonist, is a potent and efficacious intraocular pressure lowering agent in ocular hypertensive cynomolgus monkeys. In: Drug Development Research. 2014 ; Vol. 75, No. 4. pp. 211-223.
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abstract = "FR-190997 (8-[2,6-dichloro-3-[N-[(E)-4-(N-methylcarbamoyl) cinnaminoacetyl]-Nmethylamino] 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 (K i = 9.8 nM) and a relatively high potency (EC50 = 155 nM) for mobilizing intracellular Ca2+ ([Ca2+]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 (E max = 38-80{\%}) in these cells and its [Ca2+]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 posttopical 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 [Ca2+]; induces PG and pro-MMP production, and that profoundly lowers IOP by promoting UVSO in ocular hypertensive Cynomolgus monkey eyes.",
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