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
The protein kinase C (PKC) family of serine/threonine kinases is implicated in a wide variety of cellular processes. The PKC theta (PKCtheta) isoform is involved in TCR signal transduction and T cell activation and regulates T cell mediated diseases, including lung inflammation and airway hyperresponsiveness. Thus inhibition of PKCtheta enzyme activity by a small molecule represents an attractive strategy for the treatment of asthma. A PKCtheta high-throughput screening (HTS) campaign led to the identification of 4-(3-bromophenylamino)-5-(3,4-dimethoxyphenyl)-3-pyridinecarbonitrile 4a, a low microM ATP competitive PKCtheta inhibitor. Structure based hit-to-lead optimization led to the identification of 5-(3,4-dimethoxyphenyl)-4-(1H-indol-5-ylamino)-3-pyridinecarbonitrile 4p, a 70 nM PKCtheta inhibitor. Compound 4p was selective for inhibition of novel PKC isoforms over a panel of 21 serine/threonine, tyrosine, and phosphoinositol kinases, in addition to the conventional and atypical PKCs, PKCbeta, and PKCzeta, respectively. Compound 4p also inhibited IL-2 production in antiCD3/anti-CD28 activated T cells enriched from splenocytes.
Subject(s)
Indoles/pharmacology , Isoenzymes/antagonists & inhibitors , Nitriles/pharmacology , Protein Kinase C/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Pyridines/pharmacology , Animals , Crystallography, X-Ray , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Female , Indoles/chemical synthesis , Indoles/chemistry , Interleukin-2/antagonists & inhibitors , Interleukin-2/biosynthesis , Isoenzymes/deficiency , Isoenzymes/drug effects , Mice , Mice, Inbred C57BL , Mice, Knockout , Models, Molecular , Molecular Structure , Nitriles/chemical synthesis , Nitriles/chemistry , Protein Kinase C/deficiency , Protein Kinase C/drug effects , Protein Kinase C-theta , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Pyridines/chemical synthesis , Pyridines/chemistry , Spleen/cytology , Spleen/drug effects , Spleen/immunology , Stereoisomerism , Structure-Activity Relationship , T-Lymphocytes/drug effects , T-Lymphocytes/immunologyABSTRACT
The JAK-STAT3 pathway regulates genes that are important in cell proliferation and thus is a promising target for cancer therapy. A high-throughput screening (HTS) campaign using an Apo-ONE Homogenous Caspase 3/7 assay in U266 cells identified 4-oxo-1-phenyl-1,4-dihydroquinoline-3-carboxylic acid ethyl ester 4 as a potential STAT3 pathway inhibitor. Optimization of this HTS hit led to the identification of the 7-cyano analogue 8, which inhibited STAT3-Y705 phosphorylation with an EC 50 of 170 nM. Compound 8 also inhibited cytokine induced JAK activation but did not inhibit BCR-ABL activated STAT5 phosphorylation in K562 cells.
Subject(s)
Quinolones/pharmacology , STAT3 Transcription Factor/antagonists & inhibitors , Signal Transduction/drug effects , Cell Line, Tumor , Chromatography, High Pressure Liquid , Esters , Humans , Magnetic Resonance Spectroscopy , Phosphorylation , STAT3 Transcription Factor/metabolismABSTRACT
The thieno[2,3-b]pyridine-5-carbonitrile with a 5-indolylamine at C-4 and a phenyl group at C-2 had a moderate activity against PKCtheta. Optimization of the groups at C-4 and C-2 led to analog 29, which has an IC(50) value of 7.5nM for the inhibition of PKCtheta.
