Preclinical pharmacology of AL-12182, a new ocular hypotensive 11-oxa prostaglandin analog.
OBJECTIVE
The aim of this study was to determine selected in vivo ocular properties of AL-12182 (5,6-dihydro-4,5-didehydro-11-deoxy-11-oxa-16-(3-chlorophenoxy)-omega-tetranor-PGF(2alpha) isopropyl ester) and the in vitro profile of its free acid, AL-12180.


METHODS
Previously documented radioligand binding and functional assays involving human ciliary muscle cells (h-CM), human trabecular meshwork (h-TM) and other cells, and porcine ocular arteries were utilized. For in vivo procedures, we utilized rabbits, cats, and nonhuman primates to measure hyperemia, pupil diameter, and intraocular pressure (IOP), respectively.


RESULTS
AL-12180 exhibited the highest affinity for the FP-receptor (K(i) = 143 +/- 36 nM) and much lower affinity for DP-, EP(3)-, IP-, and TP-receptors, and for several nonprostanoid receptors, enzymes, neurotransmitter uptake sites, ion channels, and other regulatory sites. AL-12180 activated phospholipase C-mediated phosphoinositide hydrolysis (potency, EC(50) = 13.7-42.7 nM) through the FP-receptor in a variety of cells, such as h-CM, h-TM cells, human embryonic kidney cells expressing the cloned human ciliary body FP-receptor (HEK-FP), mouse 3T3 cells, and rat vascular smooth muscle cells. AL-8810, an FP-antagonist, blocked the effects of AL-12180 in h-CM cells (IC(50) = 8.7 microM). AL-12180 also stimulated the mobilization of intracellular Ca(2+) ([Ca(2+)](i)) in h-TM cells (EC(50) = 111 +/- 36 nM), h-CM cells (EC(50) = 11 nM), and in host cells expressing the cloned human ciliary body FP-receptor (EC(50) = 5.9 +/- 3.1 nM). AL-12180 lacked significant agonist activity at DP-, EP(2)-, EP(4)-, IP-, and TP-receptors in cell-based assays. However, AL-12180 contracted porcine central retinal and short posterior ciliary arteries in vitro with micromolar potencies that appeared to involve TP-receptor activation. in vivo, AL-12182 elicited dose-related hyperemia in the rabbit eye, miosis in the cat eye, and ocular hypotension in the nonhuman primate eye.


CONCLUSIONS
AL-12180 is a relatively potent and selective FP-receptor agonist whose isopropyl ester prodrug (AL-12182) lowers IOP by as much as 40% following topical ocular dosing in a laser-induced nonhuman primate model of ocular hypertension.
Sharif
Najam A
NA
Ophthalmology Discovery Research, Alcon Research, Ltd., Fort Worth, TX 76137, USA. naj.sharif@alconlabs.com
McLaughlin
Marsha A
MA
Kelly
Curtis R
CR
Xu
Shouxi
S
Crider
Julie Y
JY
Williams
Gary W
GW
Parker
Janet L
JL
D000818:Animals; D016466:CHO Cells; D002415:Cats; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D004353:Drug Evaluation, Preclinical; D005123:Eye / Q000098:blood supply / Q000187:drug effects; D006801:Humans; D006940:Hyperemia / Q000188:drug therapy; D007429:Intraocular Pressure / Q000187:drug effects; D008252:Macaca fascicularis; D051379:Mice; D009798:Ocular Hypertension / Q000188:drug therapy*; D009880:Ophthalmic Artery / Q000187:drug effects; D011465:Prostaglandins, Synthetic / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D011485:Protein Binding; D011817:Rabbits; D051381:Rats; D011982:Receptors, Prostaglandin / Q000378:metabolism; D013552:Swine; D041701:Swiss 3T3 Cells; D014661:Vasoconstriction / Q000187:drug effects
C500274:AL-12182; D011465:Prostaglandins, Synthetic; D011982:Receptors, Prostaglandin