ABSTRACT
We report the SAR around a series of 2,4-diaminopyrimidine-5-carboxamide inhibitors of Sky kinase. 2-Aminophenethyl analogs demonstrate excellent potency but moderate kinase selectivity, while 2-aminobenzyl analogs that fill the Ala571 subpocket exhibit good inhibition activity and excellent kinase selectivity.
Subject(s)
Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Pyrimidines/chemistry , Pyrimidines/pharmacology , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Amides/chemistry , Amides/pharmacology , Animals , Humans , Mice , Structure-Activity Relationship , Substrate SpecificityABSTRACT
Optimization of the ADME properties of a series of 2,4-diaminopyrimidine-5-carboxamide inhibitors of Sky kinase resulted in the identification of highly selective compounds with properties suitable for use as in vitro and in vivo tools to probe the effects of Sky inhibition.
Subject(s)
Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Pyrimidines/chemistry , Pyrimidines/pharmacology , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Amides/chemistry , Amides/pharmacology , Animals , Humans , Mice , Receptor Protein-Tyrosine Kinases/chemistry , Structure-Activity Relationship , Substrate SpecificityABSTRACT
Activation of the Keap1/nuclear factor erythroid 2-related factor 2 (Nrf2) pathway and consequent induction of phase 2 antioxidant enzymes is known to afford neuroprotection. Here, we present a series of novel electrophilic compounds that protect neurons via this pathway. Natural products, such as carnosic acid (CA), are present in high amounts in the herbs rosemary and sage as ortho-dihydroquinones, and have attracted particular attention because they are converted by oxidative stress to their active form (ortho-quinone species) that stimulate the Keap1/Nrf2 transcriptional pathway. Once activated, this pathway leads to the production of a series of antioxidant phase 2 enzymes. Thus, such dihydroquinones function as redox-activated 'pro-electrophiles'. Here, we explored the concept that related para-dihydroquinones represent even more effective bioactive pro-electrophiles for the induction of phase 2 enzymes without producing toxic side effects. We synthesized several novel para-hydroquinone-type pro-electrophilic compounds (designated D1 and D2) to analyze their protective mechanism. DNA microarray, PCR, and western blot analyses showed that compound D1 induced expression of heat-shock proteins (HSPs), including HSP70, HSP27, and DnaJ, in addition to phase 2 enzymes such as hemeoxygenase-1 (HO-1), NADP(H) quinine-oxidoreductase1, and the Na(+)-independent cystine/glutamate exchanger (xCT). Treatment with D1 resulted in activation of Nrf2 and heat-shock transcription factor-1 (HSF-1) transcriptional elements, thus inducing phase 2 enzymes and HSPs, respectively. In this manner, D1 protected neuronal cells from both oxidative and endoplasmic reticulum (ER)-related stress. Additionally, D1 suppressed induction of 78 kDa glucose-regulated protein (GRP78), an ER chaperone protein, and inhibited hyperoxidation of peroxiredoxin 2 (PRX2), a molecule that is in its reduced state can protect from oxidative stress. These results suggest that D1 is a novel pro-electrophilic compound that activates both the Nrf2 and HSF-1 pathways, and may thus offer protection from oxidative and ER stress.
Subject(s)
Antioxidants/metabolism , DNA-Binding Proteins/physiology , NF-E2-Related Factor 2/physiology , Neuroprotective Agents/pharmacology , Quinones/pharmacology , Retinal Pigment Epithelium/enzymology , Signal Transduction/physiology , Transcription Factors/physiology , Antioxidants/chemical synthesis , Antioxidants/physiology , Cells, Cultured , DNA-Binding Proteins/metabolism , Endoplasmic Reticulum Chaperone BiP , Heat Shock Transcription Factors , Humans , NF-E2-Related Factor 2/metabolism , Neuroprotective Agents/chemical synthesis , Oxidative Stress/drug effects , Oxidative Stress/physiology , Quinones/chemical synthesis , Retinal Pigment Epithelium/drug effects , Signal Transduction/drug effects , Transcription Factors/metabolismABSTRACT
A new adenine-substituted bromotyrosine-derived metabolite designated as aphrocallistin (1) has been isolated from the deep-water Hexactinellida sponge Aphrocallistes beatrix. Its structure was elucidated on the basis of spectral data and confirmed through a convergent, modular total synthetic route that is amenable toward future analogue preparation. Aphrocallistin inhibits the growth of a panel of human tumor cell lines with IC(50) values ranging from 7.5 to >100 microM and has been shown to induce G1 cell cycle arrest in the PANC-1 pancreatic carcinoma cell line. Aphrocallistin has been fully characterized in the NCI cancer cell line panel and has undergone in vitro ADME pharmacological profiling.
Subject(s)
Adenine/analogs & derivatives , Porifera/chemistry , Tyramine/analogs & derivatives , Adenine/chemical synthesis , Adenine/isolation & purification , Adenine/pharmacology , Animals , Candida albicans/drug effects , Cell Cycle/drug effects , Drug Screening Assays, Antitumor , Humans , Inhibitory Concentration 50 , Methicillin-Resistant Staphylococcus aureus/drug effects , Microbial Sensitivity Tests , Molecular Structure , Nuclear Magnetic Resonance, Biomolecular , Pseudomonas aeruginosa/drug effects , Tyramine/chemical synthesis , Tyramine/isolation & purification , Tyramine/pharmacologyABSTRACT
Rational replacement of the alkyne linker of mGluR5 antagonist MPEP gave 7-arylquinolines. SAR optimization gave an orally active compound with high affinity for the MPEP binding site.
Subject(s)
Drug Design , Excitatory Amino Acid Antagonists/chemistry , Excitatory Amino Acid Antagonists/pharmacology , Quinolines/chemistry , Quinolines/pharmacology , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Models, Molecular , Molecular Structure , Pyridines/chemistry , Pyridines/pharmacology , Receptor, Metabotropic Glutamate 5 , Structure-Activity RelationshipABSTRACT
A series of 1,4-benzyloxybenzylsulfanylaryl carboxylic acids were prepared and their activities for PPAR receptor subtypes (alpha, delta, and gamma) with potential indications for the treatment of dyslipidemia were investigated. Analog 13a displayed the greatest binding affinity (IC(50)=10nM) and selectivity (120-fold) for PPARdelta over PPARalpha. Many of the analogs investigated were found to be highly selective for PPARdelta and were dependent on the point of attachment of the substituent. In the 1,4-series, analog 28e was found to be the most potent (IC(50)=1.7 nM) and selective (>1000-fold) compound for PPARdelta. None of the compounds tested showed appreciable binding affinity for PPARgamma.
