FR‐190997, a Nonpeptide Bradykinin B2‐Receptor Partial Agonist, is a Potent and Efficacious Intraocular Pressure Lowering Agent in Ocular Hypertensive Cynomolgus Monkeys. Issue 4 (2nd May 2014)

• Record Type: Journal Article
• Authors: Sharif, Najam A.; Katoli, Parvaneh; Scott, Daniel; Li, Linya; Kelly, Curtis; Xu, Shouxi; Husain, Shahid; Toris, Carol; Crosson, Craig
• Is Part Of: Drug development research. Volume 75:Issue 4(2014)
• Page Start: 211
• Page End: 223
• Publication Date: 2014-05-02
• Subjects: Drug development -- Periodicals; Drugs -- Research -- Periodicals; 615.19
• DOI: 10.1002/ddr.21174
• Languages: English
• ISSNs: 0272-4391

Abstract

<abstract abstract-type="main"> <title>Abstract</title> <p> <table-wrap position="anchor" orientation="portrait"> <table border="1"> <colgroup span="1"> <col align="left" span="1" /> </colgroup> <tbody> <tr> <td align="left" rowspan="1" colspan="1">Preclinical Research</td> </tr> </tbody> </table> </table-wrap> </p> <p>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) B<sub>2</sub>‐receptor‐selective agonist, represents a novel class of ocular hypotensive agents. FR‐190997 exhibited a high affinity for the human cloned B<sub>2</sub>‐receptor (K<sub>i</sub> = 9.8 nM) and a relatively high potency (EC<sub>50</sub> = 155 nM) for mobilizing intracellular Ca<sup>2+</sup> ([Ca<sup>2+</sup>]<sub>i</sub>) 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<sub>max</sub> = 38–80%) in these cells and its [Ca<sup>2+</sup>]<sub>i</sub> — mobilizing effects were blocked by the B<sub>2</sub>‐receptor‐selective antagonists (HOE‐140, K<sub>i</sub> = 0.8–7 nM; WIN‐64338, K<sub>i</sub> = 157–425 nM). FR‐190997 stimulated the production of prostaglandins (PGs) in h‐CM and h‐TM cells (EC<sub>50</sub> = 15–19 nM; E<sub>max</sub> = 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% [<italic>P</italic> < 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 B<sub>2</sub>‐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 B<sub>2</sub>‐receptor selective partial agonist that activates phospholipase C, mobilizes [Ca<sup>2+</sup>]; induces PG and pro‐MMP production, and that profoundly lowers IOP by promoting UVSO in ocular hypertensive Cynomolgus monkey eyes.</p> </abstract>