ABSTRACT
The aim of the study was to investigate the ocular hypotensive activity of a nitric oxide (NO)-donating latanoprost, BOL-303259-X, following topical administration. The effect of BOL-303259-X (also known as NCX 116 and PF-3187207) on intraocular pressure (IOP) was investigated in monkeys with laser-induced ocular hypertension, dogs with naturally-occurring glaucoma and rabbits with saline-induced ocular hypertension. Latanoprost was used as reference drug. NO, downstream effector cGMP, and latanoprost acid were determined in ocular tissues following BOL-303259-X administration as an index of prostaglandin and NO-mediated activities. In primates, a maximum decrease in IOP of 31% and 35% relative to baseline was achieved with BOL-303259-X at doses of 0.036% (9 µg) and 0.12% (36 µg), respectively. In comparison, latanoprost elicited a greater response than vehicle only at 0.1% (30 µg) with a peak effect of 26%. In glaucomatous dogs, IOP decreased from baseline by 44% and 10% following BOL-303259-X (0.036%) and vehicle, respectively. Latanoprost (0.030%) lowered IOP by 27% and vehicle by 9%. Intravitreal injection of hypertonic saline in rabbits increased IOP transiently. Latanoprost did not modulate this response, whereas BOL-303259-X (0.036%) significantly blunted the hypertensive phase. Following BOL-303259-X treatment, latanoprost acid was significantly elevated in rabbit and primate cornea, iris/ciliary body and aqueous humor as was cGMP in aqueous humor. BOL-303259-X lowered IOP more effectively than latanoprost presumably as a consequence of a contribution by NO in addition to its prostaglandin activity. The compound is now in clinical development for the treatment of glaucoma and ocular hypertension.
Subject(s)
Antihypertensive Agents/pharmacology , Dinoprost/agonists , Disease Models, Animal , Glaucoma/drug therapy , Intraocular Pressure/drug effects , Nitric Oxide Donors/pharmacology , Nitric Oxide/metabolism , Ocular Hypertension/drug therapy , Prostaglandins F, Synthetic/pharmacology , Administration, Topical , Animals , Antihypertensive Agents/pharmacokinetics , Aqueous Humor/enzymology , Cell Line , Ciliary Body/metabolism , Cyclic GMP/metabolism , Dogs , Drug Evaluation, Preclinical , Female , Glaucoma/metabolism , Guanylate Cyclase/metabolism , Iris/metabolism , Latanoprost , Macaca fascicularis , Male , Nitric Oxide Donors/pharmacokinetics , Ocular Hypertension/metabolism , Prostaglandins F, Synthetic/pharmacokinetics , Rabbits , Rats , Tonometry, OcularABSTRACT
PURPOSE: Nitric oxide (NO) is involved in a variety of physiological processes including ocular aqueous humor dynamics by targeting mechanisms that are complementary to those of prostaglandins. Here, we have characterized a newly synthesized compound, NCX 125, comprising latanoprost acid and NO-donating moieties. METHODS: NCX 125 was synthesized and tested in vitro for its ability to release functionally active NO and then compared with core latanoprost for its intraocular pressure (IOP)-lowering effects in rabbit, dog, and nonhuman primate models of glaucoma. RESULTS: NCX 125 elicited cGMP formation (EC(50) = 3.8 + or - 1.0 microM) in PC12 cells and exerted NO-dependent iNOS inhibition (IC(50) = 55 + or - 11 microM) in RAW 264.7 macrophages. NCX 125 lowered IOP to a greater extent compared with equimolar latanoprost in: (a) rabbit model of transient ocular hypertension (0.030% latanoprost, not effective; 0.039% NCX 125, Delta(max) = -10.6 + or - 2.3 mm Hg), (b) ocular hypertensive glaucomatous dogs (0.030% latanoprost, Delta(max)= -6.7 + or - 1.2 mm Hg; 0.039% NCX 125, Delta(max) = -9.1 + or - 3.1 mm Hg), and (c) laser-induced ocular hypertensive non-human primates (0.10% latanoprost, Delta(max) = -11.9 + or - 3.7 mm Hg, 0.13% NCX 125, Delta(max) = -16.7 + or - 2.2 mm Hg). In pharmacokinetic studies, NCX 125 and latanoprost resulted in similar latanoprost-free acid exposure in anterior segment ocular tissues. CONCLUSIONS: NCX 125, a compound targeting 2 different mechanisms, is endowed with potent ocular hypotensive effects. This may lead to potential new perspectives in the treatment of patients at risk of glaucoma.
Subject(s)
Antihypertensive Agents/pharmacology , Disease Models, Animal , Glaucoma/drug therapy , Intraocular Pressure/drug effects , Nitric Oxide/metabolism , Prostaglandins F, Synthetic/pharmacology , Prostaglandins, Synthetic/pharmacology , Animals , Aqueous Humor/metabolism , Ciliary Body/metabolism , Cyclic GMP/metabolism , Dogs , Female , Glaucoma/metabolism , Iris/metabolism , Macaca fascicularis , Macrophages/drug effects , Macrophages/metabolism , Male , Nitric Oxide Synthase Type II/antagonists & inhibitors , Ocular Hypertension/drug therapy , Ocular Hypertension/metabolism , Ophthalmic Solutions/pharmacology , Prostaglandins F, Synthetic/chemical synthesis , Rabbits , Tumor Cells, Cultured/drug effects , Tumor Cells, Cultured/metabolismABSTRACT
Novel bi-functional compounds with a nitric oxide (NO)-releasing moiety bound to a dorzolamide scaffold were investigated. Several compounds were synthesized and their activity as selective carbonic anhydrase inhibitors (CAI) evaluated in vitro on recombinant hCA type I, II and IV enzyme isoforms where they showed different degrees of potency and selectivity to hCA II. A high resolution X-ray crystal structure for the CA II adduct with 8 confirmed the high affinity of this class of compounds for the enzyme. Compounds 4, 6, and 8 showed highly potent and efficacious NO-mediated properties as assessed by their vascular relaxant effect on methoxamine-precontracted rabbit aortic rings. Finally, compounds 4 and 6 exerted potent intraocular pressure (IOP) lowering effects in vivo in normotensive rabbits thereby anticipating their potential for the treatment of hypertensive glaucoma.
Subject(s)
Carbonic Anhydrase II/antagonists & inhibitors , Carbonic Anhydrase Inhibitors/therapeutic use , Glaucoma, Open-Angle/drug therapy , Nitric Oxide/chemistry , Sulfonamides/therapeutic use , Thiophenes/therapeutic use , Animals , Carbonic Anhydrase Inhibitors/chemical synthesis , Carbonic Anhydrase Inhibitors/chemistry , Crystallography, X-Ray , Drug Discovery , Models, Molecular , Molecular Structure , Rabbits , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/chemistry , Thiophenes/chemical synthesis , Thiophenes/chemistryABSTRACT
A novel class of timolol derivatives with nitric oxide (NO)-donating moieties achieved chemical stability yet under physiologically relevant conditions released timolol and NO. Hindered esters A were designed and synthesized, whose 'triggered' release relied on enzymatic hydrolysis of the nitrate ester in A to B, that in turn cyclized to liberate timolol.
