D.F. Woodward, A.H-P. Krauss, R.M.
Burk, S.W. Andrews, J. Chen, B. Brar, M.E. Garst, L.J. Kaplan, L.A. Wheeler
Lumigan (AGN 192024) is a potent and
long-acting ocular hypotensive agent in all species studied to date, including
human. The effects of graded,
once-daily doses (0.001%, 0.01%, 0.03%, 0.1%) of Lumigan on intraocular
pressure were examined in ocular normotensive dogs and monkeys and
laser-induced, ocular hypertensive monkeys. Lumigan, even at a 0.001% dose,
produced significant reductions in intraocular pressure. A 0.03% dose provided maximal efficacy,
with the effects on intraocular pressure well maintained for 24 hour post-dosing.
Pharmacological characterization of Lumigan
was extensive and involved radioligand binding and functional studies at more
than 100 targets. Lumigan had no meaningful activity at a diverse panel of
receptor subtypes, which included known anti-glaucoma drug targets as follows:
adenosine (A1, A2, A3), adrenergic (alpha-1, alpha-2, beta-1, beta-2),
cannabinoid (CB1, CB2), dopamine (D1-5), muscarinic (M1-5), prostanoid (DP,
EP1-4, FP, IP, TP), serotonin (5HT1-5HT7). Lumigan exclusively stimulated prostamide-sensitive
receptors. It is concluded that
AGN 192024 mimics the products of the prostamide pathway, a biosynthetic route
to novel ocular hypotensive substances that are natural constituents of the eye.