In:
Drug Development Research, Wiley, Vol. 75, No. 4 ( 2014-06), p. 211-223
Abstract:
Preclinical Research 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 2 ‐receptor‐selective agonist, represents a novel class of ocular hypotensive agents. FR ‐190997 exhibited a high affinity for the human cloned B 2 ‐receptor ( K i = 9.8 nM) and a relatively high potency ( EC 50 = 155 nM) for mobilizing intracellular Ca 2+ ([ Ca 2+ ] 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 [ Ca 2+ ] i — mobilizing effects were blocked by the B 2 ‐receptor‐selective antagonists ( HOE ‐140, K i = 0.8–7 nM; WIN ‐64338, K i = 157–425 nM). FR ‐190997 stimulated the production of prostaglandins ( PGs ) in h‐CM and h‐TM cells ( EC 50 = 15–19 nM; E max = 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 post‐topical ocular dosing) in ocular hypertensive eyes of consci ous Cynomolgus monkeys. This effect was reduced by bromfenac and completely blocked by a B 2 ‐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 2 ‐receptor selective partial agonist that activates phospholipase C , mobilizes [ Ca 2+ ]; induces PG and pro‐ MMP production, and that profoundly lowers IOP by promoting UVSO in ocular hypertensive Cynomolgus monkey eyes.
Type of Medium:
Online Resource
ISSN:
0272-4391
,
1098-2299
DOI:
10.1002/ddr.2014.75.issue-4
Language:
English
Publisher:
Wiley
Publication Date:
2014
detail.hit.zdb_id:
1500191-X
SSG:
15,3
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