ABSTRACT
We report here the discovery and pharmacological characterization of N-(1-benzyl-1H-pyrazol-3-yl)-2-phenylacetamide derivatives as potent, selective, brain-penetrating T-type calcium channel blockers. Optimization focused mainly on solubility, brain penetration, and the search for an aminopyrazole metabolite that would be negative in an Ames test. This resulted in the preparation and complete characterization of compound 66b (ACT-709478), which has been selected as a clinical candidate.
Subject(s)
Benzeneacetamides/chemistry , Benzeneacetamides/pharmacology , Calcium Channel Blockers/chemistry , Calcium Channel Blockers/pharmacology , Calcium Channels, T-Type/metabolism , Epilepsy, Generalized/drug therapy , Animals , Benzeneacetamides/metabolism , Benzeneacetamides/pharmacokinetics , Brain/drug effects , Brain/metabolism , Calcium Channel Blockers/metabolism , Calcium Channel Blockers/pharmacokinetics , Dogs , Drug Discovery , Epilepsy, Generalized/metabolism , Guinea Pigs , Humans , Macaca fascicularis , Pyrazoles/chemistry , Pyrazoles/pharmacology , Rats, Wistar , Structure-Activity RelationshipABSTRACT
We describe the discovery and optimization of new, brain-penetrant T-type calcium channel blockers. We present optimized compounds with excellent efficacy in a rodent model of generalized absence-like epilepsy. Along the fine optimization of a chemical series with a pharmacological target located in the CNS (target potency, brain penetration, and solubility), we successfully identified an Ames negative aminopyrazole as putative metabolite of this compound series. Our efforts culminated in the selection of compound 20, which was elected as a preclinical candidate.
Subject(s)
Calcium Channel Blockers/therapeutic use , Calcium Channels, T-Type/drug effects , Drug Discovery , Epilepsy, Generalized/drug therapy , Animals , Calcium Channels, T-Type/physiology , Disease Models, Animal , Humans , Mice , RatsABSTRACT
Bioisoteric replacement of the metabolically labile N-methyl amide group of a series of benzoxazinones with small heterocyclic rings has led to novel series of fused tricyclic benzoxazines which are potent 5-HT(1A/B/D) receptor antagonists with and without concomitant human serotonin transporter (hSerT) activity. Optimizing against multiple parameters in parallel identified 6-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazine-3-carboxamide (GSK588045) as a potent 5-HT(1A/B/D) receptor antagonist with a high degree of selectivity over human ether-a-go-go related gene (hERG) potassium channels, favorable pharmacokinetics, and excellent activity in vivo in rodent pharmacodynamic (PD) models. On the basis of its outstanding overall profile, this compound was progressed as a clinical candidate with the ultimate aim to assess its potential as a faster acting antidepressant/anxiolytic with reduced side-effect burden.
