ABSTRACT
Design, synthesis, and biological evaluation of pyridazine-based, 4-bicyclic heteroaryl-piperidine derivatives as potent stearoyl-CoA desaturase-1 (SCD1) inhibitors are described. In a chronic study of selected analog (3e) in Zucker fa/fa (ZF) rat, dose-dependent decrease of body weight gain and plasma fatty acid desaturation index (DI) in both C16 and C18 are also demonstrated. The results indicate that the plasma fatty acid DI may serve as an indicator for direct target engagement and biomarker for SCD1 inhibition.
Subject(s)
Bridged Bicyclo Compounds/chemistry , Enzyme Inhibitors/chemistry , Pyridazines/chemistry , Stearoyl-CoA Desaturase/antagonists & inhibitors , Administration, Oral , Animals , Body Weight/drug effects , Drug Design , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use , Half-Life , Humans , Mice , Microsomes, Liver/metabolism , Obesity/drug therapy , Pyridazines/pharmacokinetics , Pyridazines/pharmacology , Pyridazines/therapeutic use , Rats , Rats, Sprague-Dawley , Rats, Zucker , Stearoyl-CoA Desaturase/metabolism , Structure-Activity RelationshipABSTRACT
The asymmetric synthesis of 3,4-dihydro-2-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-5-[3-(trifluoromethoxy)phenyl]-alpha-(trifluoromethyl)-1(2H)-quinolineethanol (compound 11), a cholesteryl ester transfer protein inhibitor, is accomplished. The asymmetric center is established via the chiral reduction of ketone 4 employing Corey's (R)-Me CBS oxazaborolidine reagent. The tetrahydroquinoline core of the molecule is established via a Cu-mediated intramolecular amination reaction. The preparation of the prochiral ketone 4 has also been improved by eliminating the use of a hazardous aryltin reagent.
Subject(s)
Cholesterol Ester Transfer Proteins/antagonists & inhibitors , Quinolines/chemical synthesis , Quinolines/pharmacology , Animals , Catalysis , Cholesterol Ester Transfer Proteins/blood , Copper/chemistry , Humans , Indicators and Reagents , Ketones/chemical synthesis , Ketones/chemistry , Mice , Mice, Transgenic , Molecular Structure , Organotin Compounds/chemistry , Organotin Compounds/toxicity , Oxidation-Reduction , Quinolines/chemistry , StereoisomerismABSTRACT
Tetrahydroquinoline A is a potent inhibitor of the cholesterol ester transfer protein (CETP), a target for the treatment of low HDL-C and atherosclerosis. Low HDL-C has been identified as a key risk factor for cardiovascular disease in addition to high LDL-C, the target of the statin drugs. Tetrahydroquinoline A inhibits partially purified CETP with an IC(50) of 39nM. The preparation of a series of potent inhibitors of CETP designed around a 1,2,3,4-tetrahydroquinoline platform will be discussed.
Subject(s)
Chemistry, Pharmaceutical/methods , Cholesterol Ester Transfer Proteins/antagonists & inhibitors , Cholesterol Ester Transfer Proteins/chemistry , Quinolines/chemical synthesis , Quinolines/pharmacology , Animals , Atherosclerosis/drug therapy , Atherosclerosis/metabolism , Cardiovascular Diseases/prevention & control , Cholesterol, HDL/metabolism , Dogs , Drug Design , Haplorhini , Humans , Inhibitory Concentration 50 , Mice , Models, Chemical , Risk FactorsABSTRACT
With the goal of identifying a CETP inhibitor with high in vitro potency and optimal in vivo efficacy, a conformationally constrained molecule was designed based on the highly potent and flexible 13. The synthetic chemistry efforts led to the discovery of the potent and selective 12. In high-fat fed hamsters, human CETP transgenic mice, and cynomolgus monkeys, the in vivo efficacy of 12 for raising HDL-C was demonstrated to be comparable to torcetrapib.
Subject(s)
Cholesterol Ester Transfer Proteins/antagonists & inhibitors , Quinolines/chemistry , Quinolines/pharmacology , Administration, Oral , Animals , Cricetinae , Dietary Fats/administration & dosage , Drug Design , Humans , Macaca fascicularis , Magnetic Resonance Spectroscopy , Mice , Quinolines/chemical synthesis , Spectrometry, Mass, Electrospray IonizationABSTRACT
A biaryl pyridylfuran P(3) substituent on the hydroxyethylene isostere scaffold affords HIV protease inhibitors (PI's) with picomolar (IC(50)) potency against the protease enzymes from PI-resistant HIV-1 strains. Inclusion of a gem-dimethyl substituent afforded compound 3 with 100% oral bioavailability (dogs) and more than double the t(1/2) of indinavir. Inhibition of multiple P450 isoforms is dependent on the regiochemistry of the pyridyl nitrogen in these compounds.
Subject(s)
Drug Resistance, Viral , HIV Protease Inhibitors/chemical synthesis , HIV Protease Inhibitors/pharmacology , HIV-1/drug effects , Animals , Biological Availability , Cytochrome P-450 Enzyme Inhibitors , Dogs , HIV Protease Inhibitors/pharmacokinetics , HIV-1/enzymology , Half-Life , Indinavir/pharmacokinetics , Isoenzymes/antagonists & inhibitors , Macaca mulatta , Mutation/genetics , Structure-Activity RelationshipABSTRACT
Indinavir analogues with blocked metabolism sites show highly improved pharmacokinetic profiles in animals. The cis-aminochromanol substituted analogues exhibited excellent potency against both the wild-type (NL4-3) virus and protease inhibitor-resistant HIV strains.
Subject(s)
HIV Protease Inhibitors/chemical synthesis , HIV/drug effects , Indinavir/analogs & derivatives , Animals , Area Under Curve , Dogs , Drug Resistance , HIV Protease/drug effects , HIV Protease Inhibitors/metabolism , HIV Protease Inhibitors/pharmacokinetics , Humans , Indinavir/metabolism , Indinavir/pharmacokinetics , Inhibitory Concentration 50 , Metabolic Clearance Rate , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
A combinatorial library of 300HIV protease inhibitors has been synthesized. The library was screened against recombinant wild-type and mutant HIV-1 protease enzymes. The pharmacokinetics of the library was evaluated by dosing in dogs. Compounds that are notably more potent than indinavir and have favorable pharmacokinetic properties were identified.
