Purpose: AGN 192024
(Lumigan) is a novel, potent, and long-acting ocular hypotensive agent. In order to elucidate the pharmacology
of AGN 192024, an extensive series of in vitro studies was performed.
Methods: The in
vitro methods involved functional and radioligand binding studies on
recombinant and natural receptors. IOP was determined by pneumatonometry in
dogs (5 days, qd) and in laser-induced ocular hypertensive monkeys (single
drop).
Results and
Discussion: AGN 192024 exhibited no meaningful pharmacological activity
(IC50/EC50 > 10 microM) at a panel of greater than 100 drug targets. These included receptors that are known
anti-glaucoma drug targets as follows: adenosine (A1-3), 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). AGN 192024 exhibited activity only
in a prostamide-sensitive preparation, namely the feline iris-sphincter. Thus,
AGN 192024 appears to mimic the activity of recently discovered endogenous
substances called prostamides which are naturally occurring in the eye. AGN
192024 was a potent and efficacious ocular hypotensive agent in Beagle dogs and
cynomolgus monkeys; at a 0.03% concentration, the maximal IOP decreases were
37% and 35%, respectively. It was long-acting and a single dose produced
substantial decreases in IOP at 24 hours post-administration.