ABSTRACT
Previously disclosed C6 amido and benzimidazole dihydropyrazolopyrimidines were potent and selective blockers of IKur current. Syntheses and SAR for C6 triazolo and imidazo dihydropyrazolopyrimidines series are described. Trifluoromethylcyclohexyl N(1) triazole, compound 51, was identified as a potent and selective Kv1.5 inhibitor with an acceptable PK and liability profile.
Subject(s)
Potassium Channel Blockers/chemistry , Potassium Channels/chemistry , Pyrazoles/chemistry , Pyrimidines/chemistry , Triazoles/chemistry , Animals , Cell Line , Imidazoles/chemistry , Isomerism , Kv1.5 Potassium Channel/antagonists & inhibitors , Kv1.5 Potassium Channel/metabolism , Mice , Potassium Channel Blockers/chemical synthesis , Potassium Channel Blockers/metabolism , Potassium Channels/metabolism , Protein Binding , Pyrazoles/chemical synthesis , Pyrimidines/chemical synthesis , Pyrimidines/metabolism , Structure-Activity Relationship , Triazoles/chemical synthesisABSTRACT
Previously disclosed dihydropyrazolopyrimidines are potent and selective blockers of I(Kur) current. A potential liability with this chemotype is the formation of a reactive metabolite which demonstrated covalent binding to protein in vitro. When substituted at the 2 or 3 position, this template yielded potent I(Kur) inhibitors, with selectivity over hERG which did not form reactive metabolites. Subsequent optimization for potency and PK properties lead to the discovery of ((S)-5-(methoxymethyl)-7-(1-methyl-1H-indol-2-yl)-2-(trifluoromethyl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)((S)-2-(3-methylisoxazol-5-yl)pyrrolidin-1-yl)methanone (13j), with an acceptable PK profile in preclinical species and potent efficacy in the preclinical rabbit atrial effective refractory period (AERP) model.
Subject(s)
Kv1.5 Potassium Channel/antagonists & inhibitors , Pyrazoles/chemical synthesis , Pyrimidines/chemical synthesis , Animals , Dogs , Heart/drug effects , Heart/physiology , Humans , Pyrazoles/pharmacokinetics , Pyrazoles/pharmacology , Pyrimidines/pharmacokinetics , Pyrimidines/pharmacology , Rabbits , Rats , Refractory Period, Electrophysiological/drug effects , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Based on the scaffold of the pharmacologically selective thyromimetic 2b, structurally a close analog to KB-141 (2a), a number of novel N-acylated-alpha-amino acid derivatives were synthesized and tested in a TR radioligand binding assay as well as in a reporter cell assay. On the basis of TRbeta(1)-isoform selectivity and affinity, as well as affinity to the reporter cell assay, 3d was selected for further studies in the cholesterol-fed rat model. In this model 3d revealed an improved therapeutic window between cholesterol and TSH lowering but decreased margins versus tachycardia compared with 2a.
Subject(s)
Amino Acids/pharmacology , Molecular Mimicry , Phenyl Ethers/pharmacology , Phenylacetates/pharmacology , Receptors, Thyroid Hormone/drug effects , Amino Acids/chemistry , Animals , CHO Cells , Cholesterol, Dietary/administration & dosage , Cricetinae , Cricetulus , Ligands , Radioligand Assay , Rats , Receptors, Thyroid Hormone/metabolismABSTRACT
Bis-aryl ureas have been disclosed previously as a potent class of Raf kinase inhibitors. Modifications in the amide portion led to an improvement in aqueous solubility, an important characteristic for an oral drug. Based on this finding, we hypothesize that this portion of the molecule is directed towards the solvent in Raf-1.
Subject(s)
Enzyme Inhibitors/pharmacology , MAP Kinase Kinase Kinase 1 , Proto-Oncogene Proteins c-raf/antagonists & inhibitors , Urea/analogs & derivatives , Urea/pharmacology , Amides/chemical synthesis , Amides/pharmacology , Baculoviridae/genetics , Enzyme Inhibitors/chemical synthesis , Humans , MAP Kinase Kinase Kinases/antagonists & inhibitors , Molecular Structure , Pyridines/chemistry , Pyridines/pharmacology , Recombinant Proteins/antagonists & inhibitors , Solubility , Structure-Activity Relationship , Urea/chemical synthesisABSTRACT
Inhibitors of the MAP kinase p38 provide a novel approach for the treatment of osteoporosis, inflammatory disorders, and cancer. We have identified N-(3-tert-butyl-1-methyl-5-pyrazolyl)-N'-(4-(4-pyridinylmethyl)phenyl)urea as a potent and selective p38 kinase inhibitor in biochemical and cellular assays. This compound is orally active in two acute models of cytokine release (TNF-induced IL-6 and LPS-induced TNF) and a chronic model of arthritis (20-day murine collagen-induced arthritis).
