| Four compounds, previously unreported in the chemical literature were designed based on the primary pharmacophore 1-ethyl-1,2,3,4-tetrahydroquinoline to optimize for potency, penetration, receptor affinity and physicochemical properties. They are 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).; The pharmacological activity of the compounds was measured by their percent intraocular pressure (% IOP) reduction. The IOP recovery rate following topical administration of the compounds was determined in the rabbit IOP recovery rate assay in vivo. The results were 4.8%, 14.2%, 4.5% and 33.4% reduction for MC1, MC2, MC3 and MC4, respectively. The compounds were evaluated for their physicochemical properties, such as solubility, log DC and pKa's. MC4 was found to be most optimal of the compounds tested. Its solubility, pKa and log DC were 7.69 mg/ml, 5.05 and 2.8, respectively.; The distribution of MC1 and MC4 to various ocular tissues following infusion by the corneal and conjunctival-scleral absorption routes was studied to determine the primary route of absorption and the general order of penetration across the various tissues. The corneal route of absorption was found to be the primary route for both the compounds. Disposition studies for the active drug, MC4, were conducted using the topical infusion method through the corneal route of absorption. Tissue concentrations were determined in the infusion and the post infusion periods after tissue extractions and HPLC analysis. Data was analyzed by non-compartmental and compartmental approaches.; The zero order input rate constant (k0), first order absorption rate constant (ka), mean residence time (MRT), volume of distribution at steady state (Vss) and clearance (Cl) were obtained by the equations specific to the topical infusion method. Values for each parameter (0.0369 mug/min, 0.00041 min-1, 39.6 min, 0.72 ml and 8.4 mul/min, respectively) were consistent with the conclusion that MC4 is well absorbed, and distributed to the active site. Four classical pharmacokinetic compartmental models were proposed to fit the data, and rate equations were written for the compartments and solved in WinNonlinRTM. Parameter estimates, correlation coefficients and goodness-of-fit criteria were used to choose a proper model. A biexponential disposition adequately described the PK data and a PK/PD Link Model adequately predicted the effect compartment drug concentrations. |
