ABSTRACT
As part of an effort to identify 5-HT(1A) antagonists that did not possess typical arylalkylamine or keto/amido-alkyl aryl piperazine scaffolds, prototype compound 10a was identified from earlier work in a combined 5-HT(1A) antagonist/SSRI program. This quinolyl-piperazinyl piperidine analogue displayed potent, selective 5-HT(1A) antagonism but suffered from poor oxidative metabolic stability, resulting in low exposure following oral administration. SAR studies, driven primarily by in vitro liver microsomal stability assessment, identified compound 10b, which displayed improved oral bioavailability and lower intrinsic clearance. Further changes to the scaffold (e.g., 10r) resulted in a loss in potency. Compound 10b displayed cognitive enhancing effects in a number of animal models of learning and memory, enhanced the antidepressant-like effects of the SSRI fluoxetine, and reversed the sexual dysfunction induced by chronic fluoxetine treatment.
Subject(s)
Piperazines/chemical synthesis , Piperidines/chemical synthesis , Quinolines/chemical synthesis , Serotonin 5-HT1 Receptor Antagonists , Acetylcholine/metabolism , Administration, Oral , Amyloid beta-Protein Precursor/genetics , Animals , Antidepressive Agents/chemical synthesis , Antidepressive Agents/chemistry , Antidepressive Agents/pharmacology , Biological Availability , CHO Cells , Cerebral Cortex/metabolism , Cognition/drug effects , Cricetinae , Cricetulus , Fluoxetine/pharmacology , Hippocampus/metabolism , In Vitro Techniques , Maze Learning/drug effects , Memory/drug effects , Mice , Mice, Transgenic , Microsomes, Liver/metabolism , Nootropic Agents/chemical synthesis , Nootropic Agents/chemistry , Nootropic Agents/pharmacology , Penile Erection/drug effects , Piperazines/chemistry , Piperazines/pharmacology , Piperidines/chemistry , Piperidines/pharmacology , Quinolines/chemistry , Quinolines/pharmacology , Rats , Serotonin/metabolism , Structure-Activity RelationshipABSTRACT
Cysteine-dependant aspartyl protease (caspase) activation has been implicated as a part of the signal transduction pathway leading to apoptosis. It has been postulated that caspase-3 inhibition could attenuate cell damage after an ischemic event and thereby providing for a novel neuroprotective treatment for stroke. As part of a program to develop a small molecule inhibitor of caspase-3, a novel series of 3,4-dihydropyrimido(1,2-a)indol-10(2H)-ones (pyrimidoindolones) was identified. The synthesis, biological evaluation and structure-activity relationships of the pyrimidoindolones are described.
