ABSTRACT
Recently, it has been reported that 5-HT2 receptor agonists effectively reduce intraocular pressure (IOP) in a nonhuman primate model of glaucoma. Although 1-[(2S)-2-aminopropyl]indazol-6-ol (AL-34662) was shown to have good efficacy in this nonhuman primate model of ocular hypertension as well as a desirable physicochemical and permeability profile, subsequently identified cardiovascular side effects in multiple species precluded further clinical evaluation of this compound. Herein, we report selected structural modifications that resulted in the identification of (8R)-1-[(2S)-2-aminopropyl]-8,9-dihydro-7H-pyrano[2,3-g]indazol-8-ol (13), which displayed an acceptable profile to support advancement for further preclinical evaluation as a candidate for proof-of-concept studies in humans.
Subject(s)
Indazoles/chemical synthesis , Indazoles/therapeutic use , Ocular Hypertension/drug therapy , Serotonin 5-HT2 Receptor Agonists/therapeutic use , Administration, Topical , Animals , Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Benzophenones/administration & dosage , Benzophenones/therapeutic use , Bromobenzenes/administration & dosage , Bromobenzenes/therapeutic use , Cornea/metabolism , Glaucoma/drug therapy , HT29 Cells , Humans , In Vitro Techniques , Indazoles/adverse effects , Indicators and Reagents , Intraocular Pressure/drug effects , Macaca fascicularis , Permeability , Rats , Receptors, Adrenergic, alpha/metabolism , Receptors, Serotonin/metabolism , Serotonin 5-HT2 Receptor Agonists/adverse effects , Structure-Activity RelationshipABSTRACT
A series of 2,3,6-pyrazine Rho Kinase inhibitors were optimized for in vivo activity for topical ocular dosing. Modifications of the 2-(piperazin-1-yl)pyrazine derivatives produced compounds with improved solubility and physicochemical properties. Modifications of the 6-pyrazine substituent led to improvements in in vitro potency. Compound 9 had the best in vitro and in vivo potency of EC50=260 nM with a 30% reduction of IOP in a non-human primate model at a dose of 0.33%.
Subject(s)
Glaucoma/drug therapy , Protein Kinase Inhibitors/therapeutic use , Pyrazines/chemical synthesis , Pyrazines/therapeutic use , rho-Associated Kinases/antagonists & inhibitors , Animals , Disease Models, Animal , Dose-Response Relationship, Drug , Guinea Pigs , Humans , Inhibitory Concentration 50 , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Pyrazines/chemistry , Pyrazines/pharmacology , Pyridines/chemistry , Pyridines/pharmacology , Pyridines/therapeutic useABSTRACT
A novel series of 15-fluoro prostaglandins with phenoxy termination of the omega-chain was synthesized and evaluated for binding and functional activation of the prostaglandin FP receptor in vitro and for side effect potential and topical ocular hypotensive efficacy in vivo. Compounds with the 15alpha-fluoride relative stereochemistry displayed EC50 values of Subject(s)
Fluorides/chemistry
, Ocular Hypotension/drug therapy
, Prostaglandins/chemistry
, Prostaglandins/pharmacology
, Receptors, Prostaglandin/agonists
, Administration, Topical
, Animals
, Cats
, Haplorhini
, Molecular Structure
, Prostaglandins/chemical synthesis
, Prostaglandins/metabolism
, Rabbits
, Receptors, Prostaglandin/chemistry
, Receptors, Prostaglandin/metabolism
ABSTRACT
A series of prostaglandin DP agonists containing a 3-oxa-15-cyclohexyl motif was synthesized and evaluated in several in vitro and in vivo biological assays. The reference compound ZK 118.182 (9beta-chloro-15-cyclohexyl-3-oxa-omega-pentanor PGF(2alpha)) is a potent full agonist at the prostaglandin DP receptor. Saturation of the 13,14 olefin affords AL-6556, which is less potent but is still a full agonist. Replacement of the 9-chlorine with a hydrogen atom or inversion of the carbon 15 stereochemistry also reduces affinity. In in vivo studies ZK 118.182 lowers intraocular pressure (IOP) upon topical application in the ocular hypertensive monkey. Ester, 1-alcohol, and selected amide prodrugs of the carboxylic acid enhance in vivo potency, presumably by increasing bioavailability. The clinical candidate AL-6598, the isopropyl ester prodrug of AL-6556, produces a maximum 53% drop in monkey IOP with a 1 microg dose (0.003% w/w) using a twice-daily dosing regime. Synthetically, AL-6598 was accessed from known intermediate 1 using a novel key sequence to install the cis allyl ether in the alpha chain, involving a selective Swern oxidative desilylation of a primary silyl ether in the presence of a secondary silyl ether. In this manner, 136 g of AL-6598 was synthesized under GMP conditions for evaluation in phase I clinical trials.
