ABSTRACT
The discovery, synthesis and biological evaluation of a novel series of 7-isoxazoloquinolines is described. Several analogs are shown to increase ApoA1 expression within the nanomolar range in the human hepatic cell line HepG2.
Subject(s)
Apolipoprotein A-I/metabolism , Drug Discovery , Heterocyclic Compounds, 4 or More Rings/chemistry , Heterocyclic Compounds, 4 or More Rings/pharmacology , Nuclear Proteins/antagonists & inhibitors , Quinolines/chemistry , Up-Regulation/drug effects , Animals , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacology , Hep G2 Cells , Histone Acetyltransferases , Histone Chaperones , Humans , Inhibitory Concentration 50 , Mice , Mice, Inbred BALB C , Nerve Tissue Proteins , Nuclear Proteins/metabolism , Quinolines/pharmacology , Rats , Structure-Activity RelationshipABSTRACT
A novel series of quinoline isoxazole BET family bromodomain inhibitors are discussed. Crystallography is used to illustrate binding modes and rationalize their SAR. One member, I-BET151 (GSK1210151A), shows good oral bioavailability in both the rat and minipig as well as demonstrating efficient suppression of bacterial induced inflammation and sepsis in a murine in vivo endotoxaemia model.
Subject(s)
Heterocyclic Compounds, 4 or More Rings/chemistry , Isoxazoles/chemical synthesis , Nerve Tissue Proteins/antagonists & inhibitors , Quinolines/chemical synthesis , Animals , Binding Sites , Crystallography, X-Ray , Guinea Pigs , Heterocyclic Compounds, 4 or More Rings/metabolism , Inflammation/drug therapy , Isoxazoles/chemistry , Isoxazoles/pharmacology , Mice , Models, Molecular , Protein Binding/drug effects , Quinolines/chemistry , Quinolines/pharmacology , RatsABSTRACT
RIP1 kinase regulates necroptosis and inflammation and may play an important role in contributing to a variety of human pathologies, including inflammatory and neurological diseases. Currently, RIP1 kinase inhibitors have advanced into early clinical trials for evaluation in inflammatory diseases such as psoriasis, rheumatoid arthritis, and ulcerative colitis and neurological diseases such as amyotrophic lateral sclerosis and Alzheimer's disease. In this paper, we report on the design of potent and highly selective dihydropyrazole (DHP) RIP1 kinase inhibitors starting from a high-throughput screen and the lead-optimization of this series from a lead with minimal rat oral exposure to the identification of dihydropyrazole 77 with good pharmacokinetic profiles in multiple species. Additionally, we identified a potent murine RIP1 kinase inhibitor 76 as a valuable in vivo tool molecule suitable for evaluating the role of RIP1 kinase in chronic models of disease. DHP 76 showed efficacy in mouse models of both multiple sclerosis and human retinitis pigmentosa.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Nuclear Pore Complex Proteins/antagonists & inhibitors , Pyrazoles/chemical synthesis , Pyrazoles/pharmacology , RNA-Binding Proteins/antagonists & inhibitors , Animals , Biological Availability , Cell Line , Chronic Disease , Drug Design , Encephalomyelitis, Autoimmune, Experimental/drug therapy , Enzyme Inhibitors/pharmacokinetics , Haplorhini , High-Throughput Screening Assays , Humans , Mice , Mice, Inbred C57BL , Models, Molecular , Multiple Sclerosis/drug therapy , Pyrazoles/pharmacokinetics , Rats , Retinitis Pigmentosa/drug therapy , Structure-Activity RelationshipABSTRACT
We describe the discovery of novel potent inhibitors of 2,3-oxidosqualene:lanosterol cyclase inhibitors (OSCi) from a focused pharmacophore-based screen. Optimization of the most tractable hits gave a series of compounds showing inhibition of cholesterol biosynthesis at 2mg/kg in the rat with distinct pharmacokinetic profiles. Two compounds were selected for toxicological study in the rat for 21 days in order to test the hypothesis that low systemic exposure could be used as a strategy to avoid the ocular side effects previously described with OSCi. We demonstrate that for this series of inhibitors, a reduction of systemic exposure is not sufficient to circumvent cataract liabilities.
Subject(s)
Cataract/enzymology , Dyslipidemias/enzymology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Eye/drug effects , Intramolecular Transferases/antagonists & inhibitors , Animals , Anticholesteremic Agents/adverse effects , Anticholesteremic Agents/chemical synthesis , Anticholesteremic Agents/pharmacokinetics , Cataract/chemically induced , Cataract/drug therapy , Cell Line, Tumor , Dyslipidemias/chemically induced , Enzyme Inhibitors/adverse effects , Eye/metabolism , Female , Humans , Liver/drug effects , Liver/metabolism , Male , Oxazoles/pharmacokinetics , Oxazoles/therapeutic use , Piperazines/adverse effects , Piperazines/chemical synthesis , Piperazines/pharmacokinetics , Piperidines/pharmacokinetics , Piperidines/therapeutic use , Rats , Rats, Sprague-DawleyABSTRACT
The peroxisome proliferator activated receptors PPARalpha, PPARgamma, and PPARdelta are ligand-activated transcription factors that play a key role in lipid homeostasis. The fibrates raise circulating levels of high-density lipoprotein cholesterol and lower levels of triglycerides in part through their activity as PPARalpha agonists; however, the low potency and restricted selectivity of the fibrates may limit their efficacy, and it would be desirable to develop more potent and selective PPARalpha agonists. Modification of the selective PPARdelta agonist 1 (GW501516) so as to incorporate the 2-aryl-2-methylpropionic acid group of the fibrates led to a marked shift in potency and selectivity toward PPARalpha agonism. Optimization of the series gave 25a, which shows EC50 = 4 nM on PPARalpha and at least 500-fold selectivity versus PPARdelta and PPARgamma. Compound 25a (GW590735) has been progressed to clinical trials for the treatment of diseases of lipid imbalance.
Subject(s)
Cholesterol, HDL/blood , PPAR alpha/agonists , Propionates/chemical synthesis , Thiazoles/chemical synthesis , Animals , Apolipoprotein A-I/genetics , Cholesterol, VLDL/blood , Crystallography, X-Ray , Dogs , Dyslipidemias/blood , Dyslipidemias/drug therapy , Humans , Ligands , Mice , Mice, Inbred C57BL , Mice, Transgenic , Models, Molecular , PPAR alpha/chemistry , Propionates/pharmacokinetics , Propionates/pharmacology , Protein Structure, Tertiary , Rats , Rats, Wistar , Structure-Activity Relationship , Thiazoles/pharmacokinetics , Thiazoles/pharmacology , Triglycerides/bloodABSTRACT
AMP-activated protein kinase (AMPK) is an evolutionarily conserved fuel-sensing enzyme that is activated in shortage of energy and suppressed in its surfeit. AMPK activation stimulates fatty acid oxidation, enhances insulin sensitivity, alleviates hyperglycemia and hyperlipidemia, and inhibits proinflammatory changes. Thus, AMPK is a well-received therapeutic target for type 2 diabetes and other metabolic disorders. Here, we will report the discovery of pyrrolopyridone derivatives as AMPK direct activators. We will illustrate the synthesis and structure-activity relationships of the series as well as some pharmacokinetic results. Some compounds exhibited encouraging oral exposure and were evaluated in a mouse diabetic model. Compound 17 showed oral activity at 30 mg/kg on blood glucose.