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.
Subject(s)
Azabicyclo Compounds/pharmacokinetics , Organophosphonates/pharmacokinetics , Prodrugs/pharmacokinetics , Administration, Oral , Animals , Azabicyclo Compounds/administration & dosage , Bile/metabolism , Biological Availability , Diphosphonates/chemical synthesis , Diphosphonates/pharmacokinetics , Drug Stability , Gastric Juice/metabolism , Male , Organophosphonates/administration & dosage , Rats , Rats, Sprague-Dawley , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitorsABSTRACT
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.
