Prodrugs of perzinfotel with improved oral bioavailability.

Previous studies with perzinfotel (1), a potent, selective, competitive NMDA receptor antagonist, showed it to be efficacious in inflammatory and neuropathic pain models. To increase the low oral bioavailability of 1 (3-5%), prodrug derivatives (3a-h) were synthesized and evaluated. The oxymethylene-spaced diphenyl analogue 3a demonstrated good stability at acidic and neutral pH, as well as in simulated gastric fluid. In rat plasma, 3a was rapidly converted to 1 via 2a. Pharmacokinetic studies indicated that the amount of systemic exposure of 1 produced by a 10 mg/kg oral dose of 3a was 2.5-fold greater than that produced by a 30 mg/kg oral dose of 1. Consistent with these results, 3a was significantly more potent and had a longer duration of activity than 1 following oral administration in a rodent model of inflammatory pain. Taken together, these results demonstrate that an oxymethylene-spaced prodrug approach increased the bioavailability of 1.

Advances toward new antidepressants with dual serotonin transporter and 5-HT1A receptor affinity within a class of 3-aminochroman derivatives. Part 2.

Novel compounds combining a 5-HT 1A moiety (3-aminochroman scaffold) and a 5-HT transporter (indole analogues) linked through a common basic nitrogen via an alkyl chain attached at the 1- or 3-position of the indole were evaluated for dual affinity at both the 5-HT reuptake site and the 5-HT 1A receptor. Compounds of most interest were found to have a 5-carbamoyl-8-fluoro-3-amino-3,4-dihydro-2 H-1-benzopyran linked to a 3-alkylindole (straight chain), more specifically substituted with a 5-fluoro (( R)-(-)- 35c), 5-cyano ((-)- 52a), or 5,7-difluoro ((-)- 52g). Several factors contributed to 5-HT 1A affinity, serotonin rat transporter affinity, and functional antagonism in vitro. Although most of our analogues showed good to excellent affinities at both targets, specific features such as cyclobutyl substitution on the basic nitrogen and stereochemistry at the 3-position of the chroman moiety seemed necessary for antagonism at the 5-HT 1A receptor. Branched linkers seemed to impart antagonism even as racemates; however, the potency of these analogues in the functional assay was not desirable enough to further pursue these compounds.

Characterization of two novel N-methyl-D-aspartate antagonists: EAA-090 (2-[8,9-dioxo-2,6-diazabicyclo [5.2.0]non-1(7)-en2-yl]ethylphosphonic acid) and EAB-318 (R-alpha-amino-5-chloro-1-(phosphonomethyl)-1H-benzimidazole-2-propanoic acid hydrochloride).

Two novel N-methyl-d-aspartate (NMDA) antagonists with unique chemical structures, EAA-090 (2-[8,9-dioxo-2, 6-diazabicyclo[5.2.0]non-1(7)-en2-yl]ethylphosphonic acid) and EAB-318 (R-alpha-amino-5-chloro-1-(phosphonomethyl)-1H-benzimidazole-2-propanoic acid hydrochloride), were compared with CGS-19755 (Selfotel) in ligand binding, electrophysiology, and neuroprotection assays. CGS-19755, EAA-090 and EAB-318 inhibited [(3)H]3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid binding to NMDA receptors with IC(50) values of 55, 28, and 7.9 nM, respectively. All three compounds decreased the duration of spontaneous synaptic currents and inhibited NMDA-activated currents in rat hippocampal neurons. IC(50) values for inhibition of current induced by 10 microM NMDA were 795, 477, and 69 nM for CGS-19755, EAA-090, and EAB-318, respectively. The NMDA antagonists protected chick embryo retina slices and cultured rat hippocampal and cortical neurons from glutamate- and NMDA-induced neurotoxicity. In experiments in which different NMDA receptor splice variants and subtypes were expressed in Xenopus oocytes, all three antagonists preferentially blocked NMDA-elicited currents mediated by N-methyl-d-aspartate receptor (NR)1 splice variants containing the N-terminal insertion. They also favored NR2A-versus NR2B- or NR2C-containing NMDA receptors, with EAA-090 showing the greatest selectivity. EAA-090 was 10 times more potent at blocking NR2A-versus NR2B- or NR2C-containing NMDA receptors. In addition to being the most potent NMDA antagonist, EAB-318 inhibited alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate receptors. The combination of NMDA and AMPA/kainate block enabled EAB-318 to protect neurons against ischemia induced cell death.

Synthesis, characterization and evaluation of pro-drugs of VLA-4 antagonists.

A pro-drug strategy to identify orally efficacious VLA-4 antagonists is described. Potential pro-drugs were evaluated for their physical chemical characteristics and in vitro properties, including solubility, stability, permeability and plasma stability. Based on this characterization, promising compounds were identified for in vivo pharmacokinetic evaluation. These studies resulted in the identification of a pro-drug that exhibited desirable blood levels in PK studies in several different species.