ABSTRACT
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
A series of dihydropyrazole derivatives was developed as potent, selective, and brain-penetrating T-type calcium channel blockers. An optimized derivative, compound 6c, was advanced to in vivo studies, where it demonstrated efficacy in the WAG/Rij rat model of generalized nonconvulsive, absence-like epilepsy. Compound 6c was not efficacious in the basolateral amygdala kindling rat model of temporal lobe epilepsy, and it led to prolongation of the PR interval in ECG recordings in rodents.
Subject(s)
Anticonvulsants/chemistry , Anticonvulsants/therapeutic use , Calcium Channel Blockers/chemistry , Calcium Channel Blockers/therapeutic use , Epilepsy/drug therapy , Pyrazoles/chemistry , Pyrazoles/therapeutic use , Animals , Anticonvulsants/pharmacokinetics , Brain/drug effects , Brain/metabolism , Brain/physiopathology , Calcium Channel Blockers/pharmacokinetics , Calcium Channels, T-Type/metabolism , Disease Models, Animal , Dogs , Electroencephalography , Epilepsy/metabolism , Epilepsy/physiopathology , Humans , Kindling, Neurologic/drug effects , Male , Pyrazoles/pharmacokinetics , Rats, WistarABSTRACT
A series of acyloxyalkyl and amidooxyalkyl ketones appended to a carbobenzyloxy aspartic acid core have been prepared. The most potent of these new inhibitors was 4i with a K(i) of 0.5 microM. These two series provide an improved understanding of the binding requirements for the hydrophobic prime side of ICE.
Subject(s)
Caspase Inhibitors , Cysteine Proteinase Inhibitors/pharmacology , Ketones/pharmacology , Humans , Models, Molecular , Monocytes/drug effectsABSTRACT
A systematic investigation of the S3 sub-pocket activity requirements was conducted. It was observed that linear and sterically small side chain substituents are preferred in the S3 sub-pocket for optimal renin inhibition. Polar groups in the S3-sub-pocket were not well tolerated and caused a reduction in renin inhibitory activity. Further, compounds with clog P's < or = 3 demonstrated a dramatic reduction in CYP3A4 inhibitory activity.
Subject(s)
Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Piperazines/chemistry , Piperazines/pharmacology , Renin/antagonists & inhibitors , Crystallography, X-Ray , Cytochrome P-450 CYP3A , Cytochrome P-450 Enzyme System/drug effects , Enzyme Inhibitors/chemical synthesis , Humans , Models, Molecular , Molecular Structure , Piperazines/chemical synthesis , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Ketopiperazine 2 was designed from a previously published analog. Compound 2 was shown to be a novel, potent inhibitor of renin that, when administered orally, lowered blood pressure in a hypertensive double transgenic (human renin and angiotensinogen) mouse model. Compound 2 was further optimized to sub-nanomolar potency by designing an analog that addressed the S3 sub-pocket of the renin enzyme (16).
Subject(s)
Enzyme Inhibitors/pharmacology , Piperazines/pharmacology , Renin/antagonists & inhibitors , Animals , Blood Pressure/drug effects , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Mice , Mice, Transgenic , Molecular Structure , Piperazines/chemical synthesis , Piperazines/chemistry , Structure-Activity RelationshipABSTRACT
[reaction: see text] Chiral 1-aryl-6-(hydroxymethyl)-2-ketopiperazines can be prepared via an operationally simple, 6-exo epoxide ring-opening cyclization to form the ketopiperazine C6-N1 bond in high yields and with excellent enantiomeric purity.
