title: Ocular hypotensive action of a novel tetrahydroquinoline analog in rabbit: physicochemical evaluation.
abstract: Four new molecular entities, N-ethyl-1,4-benzoxazine (MC1), 1-ethyl-6-hydroxymethyl-1,2,3,4-tetrahydroquinoline (MC2), (R,S)-1-ethyl-6-fluoro-2-methyl-1,2,3,4-tetrahydroquinoline (MC3), and 1-ethyl-6-fluoro-1,2,3,4-tetrahydroquinoline MC4, based on the primary pharmacophore 1-ethyl-1,2,3,4-tetrahydroquinoline, were synthesized and tested for their physicochemical properties and pharmacological activities. The ocular hypotensive action was measured as percent intraocular pressure (%IOP) reduction, following topical administration in rabbit IOP recovery rate assay in vivo. The results were 4.8%, 14%, 4.5%, and 33% reduction for MC1, MC2, MC3, and MC4, respectively, with MC4 being the only statistically significant potent compound. The physicochemical properties such as solubility, distribution coefficient, and pKa were then determined in order to explain their pharmacological activities or lack thereof. MC4, the active compound, showed the highest solubility in pH 7.4 buffer, and in conjunction with ionization and distribution coefficient values, is expected to easily penetrate through the lipophilic corneal epithelium in comparison with the other compounds. Although the in vivo potency of MC4 can be attributed at least in part to its optimum physicochemical properties, it is important to note that differences in the receptor binding/potency, pharmacokinetic properties, and transporter interaction can also play a role in explaining the biological activity.
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Hoffmann-La Roche Inc., Nutley, New Jersey 07110, USA. chandrasena.pamulapati@roche.com
authors.forename: Chandrasena R
authors.initials: CR
authors.lastname: Pamulapati
authors.forename: Ronald D
authors.initials: RD
authors.lastname: Schoenwald
mesh_terms: D060433:Administration, Ophthalmic; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004353:Drug Evaluation, Preclinical; D019573:Epithelium, Corneal / Q000187:drug effects; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007429:Intraocular Pressure / Q000187:drug effects; D015814:Ocular Hypotension / Q000188:drug therapy*; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D011817:Rabbits; D012995:Solubility
chemical_list: D011804:Quinolines; C542964:1,2,3,4-tetrahydroquinoline