ABSTRACT
On the basis of the previously reported benzimidazole 1,3'-bipyrrolidine benzamides (1), a series of related pyrrolidin-3-yl-N-methylbenzamides were synthesized and evaluated as H(3) receptor antagonists. In particular, compound 32 exhibits potent H(3) receptor binding affinity, improved pharmaceutical properties and a favorable in vivo profile.
Subject(s)
Benzamides/chemical synthesis , Benzamides/pharmacology , Drug Design , Histamine H3 Antagonists/chemical synthesis , Histamine H3 Antagonists/pharmacology , Pyrrolidines/chemical synthesis , Pyrrolidines/pharmacology , Animals , Benzamides/chemistry , Benzamides/pharmacokinetics , Brain/metabolism , Cognition Disorders/drug therapy , Cognition Disorders/physiopathology , Diabetes Insipidus/drug therapy , Diabetes Insipidus/metabolism , Disease Models, Animal , Histamine H3 Antagonists/chemistry , Histamine H3 Antagonists/pharmacokinetics , Histocompatibility Antigens/metabolism , Humans , Intracellular Signaling Peptides and Proteins , Microsomes, Liver/metabolism , Molecular Targeted Therapy , Protein Binding , Pyrrolidines/chemistry , Pyrrolidines/pharmacokinetics , Rats , Stereoisomerism , Structure-Activity Relationship , Tripartite Motif ProteinsABSTRACT
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.
