ABSTRACT
Despite the availability of numerous antiepileptic drugs, 20-30% of epileptic patients are pharmacoresistant with seizures not appropriately controlled. Consequently, new strategies to address this unmet medical need are required. T-type calcium channels play a key role in neuronal excitability and burst firing, and selective triple T-type calcium channel blockers could offer a new way to treat various CNS disorders, in particular epilepsy. Herein we describe the identification of new 1,4-benzodiazepines as brain penetrant and selective triple T-type calcium channel blockers. From racemic hit 4, optimization work led to the preparation of pyridodiazepine 31c with improved physicochemical properties, solubility, and metabolic stability. The racemic mixture was separated by chiral preparative HPLC, and the resulting lead compound (3R,5S)-31c showed promising efficacy in the WAG/Rij-rat model of generalized nonconvulsive absence-like epilepsy.
Subject(s)
Brain/drug effects , Calcium Channel Blockers/pharmacology , Calcium Channels, T-Type/metabolism , Animals , Brain/metabolism , Calcium Channel Blockers/chemistry , Calcium Channel Blockers/metabolism , Dose-Response Relationship, Drug , HEK293 Cells , Humans , Male , Microsomes, Liver/chemistry , Microsomes, Liver/metabolism , Molecular Structure , Rats , Rats, Inbred Strains , Seizures/drug therapy , Structure-Activity RelationshipABSTRACT
Smoothened (Smo) antagonists are emerging as new therapies for the treatment of neoplasias with aberrantly reactivated hedgehog (Hh) signaling pathway. A novel series of 4-[3-(quinolin-2-yl)-1,2,4-oxadiazol-5-yl]piperazinyl ureas as smoothened antagonists was recently described, herein the series has been further optimized through the incorporation of a basic amine into the urea. This development resulted in identification of some exceptionally potent smoothened antagonists with low serum shifts, however, reductive ring opening on the 1,2,4-oxadiazole in rats limits the applicability of these compounds in in vivo studies.
Subject(s)
Amides/pharmacology , Piperazines/pharmacology , Receptors, G-Protein-Coupled/antagonists & inhibitors , Amides/chemical synthesis , Amides/chemistry , Molecular Structure , Piperazines/chemical synthesis , Piperazines/chemistry , Smoothened Receptor , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The Hedgehog (Hh-) signalling pathway is a key developmental pathway and there is a growing body of evidence showing that this pathway is aberrantly reactivated in a number of human tumors. Novel agents capable of inhibiting this pathway are sought, and an entirely novel series of smoothened (Smo) antagonists capable of inhibiting the pathway have been identified through uHTS screening. Extensive exploration of the scaffold identified the key functionalities necessary for potency, enabling potent nanomolar Smo antagonists like 91 and 94 to be developed. Optimization resulted in the most advanced compounds displaying low serum shift, clean off-targets profile, and moderate clearance in both rats and dogs. These compounds are valuable tools with which to probe the biology of the Hh-pathway.
Subject(s)
Hedgehog Proteins/antagonists & inhibitors , Signal Transduction/drug effects , Urea/pharmacology , Animals , Dogs , Dose-Response Relationship, Drug , Hedgehog Proteins/metabolism , Humans , Microsomes/drug effects , Microsomes/metabolism , Molecular Structure , Rats , Stereoisomerism , Structure-Activity Relationship , Urea/analogs & derivatives , Urea/chemistryABSTRACT
A novel hexahydrobenzonaphthyridinone PARP-1 pharmacophore is reported, subsequent SAR exploration around this scaffold led to selective PARP-1 inhibitors with low nanomolar enzyme potency, displaying good cellular activity and promising rat PK properties.
Subject(s)
Enzyme Inhibitors/chemistry , Naphthyridines/chemistry , Poly(ADP-ribose) Polymerase Inhibitors , Animals , Drug Discovery , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Microsomes, Liver/metabolism , Naphthyridines/chemical synthesis , Naphthyridines/pharmacokinetics , Poly(ADP-ribose) Polymerases/metabolism , Rats , Structure-Activity RelationshipABSTRACT
Herein we describe the discovery of a novel series of pyrrolo[1,2-a]pyrazin-1(2H)-one PARP inhibitors. Optimization led to compounds that display excellent PARP-1 enzyme potency and inhibit the proliferation of BRCA deficient cells in the low double-digit nanomolar range showing excellent selectivity over BRCA proficient cancer cells.
Subject(s)
Poly(ADP-ribose) Polymerase Inhibitors , Pyrazines/chemistry , Pyrazines/metabolism , Animals , BRCA1 Protein/deficiency , BRCA1 Protein/metabolism , Cell Line, Tumor , Crystallography, X-Ray , HeLa Cells , Humans , Indolizines/chemistry , Indolizines/metabolism , Microsomes, Liver/drug effects , Microsomes, Liver/enzymology , Poly (ADP-Ribose) Polymerase-1 , Poly(ADP-ribose) Polymerases/metabolism , Protein Binding/physiology , Rats , Structure-Activity RelationshipABSTRACT
We describe an extensive SAR study in the 6-[4-fluoro-3-(substituted)benzyl]-4,5-dimethylpyridazin-3(2H)-one series which led to the identification of potent PARP-1 inhibitors, capable of inhibiting the proliferation of BRCA-1 deficient cancer cells in the low nanomolar range, and displaying >100-fold selectivity over the BRCA wild type counterparts. The series of compounds was devoid of hERG channel activity, and CYP inhibition and induction liabilities. Several analogs were stable in rat and human liver microsomes and displayed moderate rat clearance, with urinary excretion of parent as the major route of elimination.
