phxa-85 and Glaucoma

Lowering of intra-ocular pressure is the primary pharmacologic approach for the treatment of glaucoma and a number of distinct mechanisms of action have been clinically validated. Targeting of multiple mechanisms in combination therapies has proven effective both clinically and commercially although potential improvements with regards to efficacy, tolerability and dosing frequency remain. Application of Theravance's multivalent approach to drug discovery towards linked dual-pharmacology prostaglandin F receptor (FP) agonist/carbonic anhydrase (CA)-II inhibitor compounds is described. Compound 29 exhibits weak potency (pEC(50)=5.7, IA>1.0) as an FP agonist with high binding affinity (pK(i)=8.1) to the CA-II enzyme, and has comparable corneal permeability to the CA-II inhibitor dorzolamide.

Topics: Carbonic Anhydrase Inhibitors; Drug Discovery; Glaucoma; Humans; Models, Molecular; Prostaglandins F, Synthetic; Receptors, Prostaglandin

FP-Class prostaglandin analogs have demonstrated utility for the treatment of glaucoma and ocular hypertension. A series of novel FP prostaglandin analogs was designed to optimize topical ocular activity and reduce ocular side-effects by replacing 13-carbon with oxygen. A facile synthesis was successfully developed for synthesis of the 13-oxa prostaglandins from the commercially available Corey aldehyde benzoate. Among the compounds synthesized, AL-16082 was the most potent prostaglandin FP agonist in vitro. In a prostaglandin FP receptor-linked second-messenger assay, phosphoinositide (PI) turnover, it exhibited a potency value (EC(50)) of 1.9 nM (78% max. response relative to fluprostenol). The isopropyl ester of AL-16082, compound AL-16049, significantly lowered intraocular pressure (IOP) in the ocular hypertensive monkey eyes by 30%. In the study of acute ocular irritation response in New Zealand albino rabbits, AL-16049 produced lower incidence of hyperemia, swelling, and discharge than PGF(2alpha) (1 microg), and a similar incidence of hyperemia, swelling, and discharge to latanoprost (1.8 microg). AL-16049 also produced no signs of ocular irritation or discomfort in the cat at the doses evaluated.

Topics: Administration, Topical; Animals; Cats; Dinoprost; Drug Discovery; Eye Diseases; Glaucoma; Haplorhini; Hypertension; Intraocular Pressure; Prostaglandins F, Synthetic; Prostaglandins, Synthetic; Rabbits; Structure-Activity Relationship

Topics: Animals; Astrocytes; Cells, Cultured; CHO Cells; Ciliary Body; Cricetinae; Cricetulus; Dinoprost; Dinoprostone; Glaucoma; Humans; Intraocular Pressure; Lens, Crystalline; Models, Biological; Neuroblastoma; Rabbits; Rats; Receptors, Prostaglandin; Recombinant Fusion Proteins; Transfection; Tumor Cells, Cultured

A series of phenyl-substituted analogues of prostaglandin F2 alpha (PGF2 alpha) were prepared and evaluated for ocular hypotensive effect and side effects in different animal models. In addition, the activity of the analogues on FP receptors was studied in vitro. The results were compared with those of PGF2 alpha and its isopropyl ester. The phenyl-substituted PGF2 alpha analogues exhibited good intraocular pressure reducing effect, were more selective, and exhibited a much higher therapeutic index in the eye than PGF2 alpha or its isopropyl ester. The analogues exhibited high activity on FP receptors in a stereoselective manner for the 15 alpha-hydroxyl group.

Topics: Animals; Cats; Dinoprost; Female; Glaucoma; Intraocular Pressure; Macaca fascicularis; Muscle Contraction; Ophthalmic Solutions; Rabbits; Species Specificity; Structure-Activity Relationship