ABSTRACT
The development of 2-phenylbenzoxazoles as inhibitors of cholesteryl ester transfer protein (CETP) is described. Efforts focused on finding suitable replacements for the central piperidine with the aim of reducing hERG binding: a main liability of our benchmark benzoxazole (1a). Replacement of the piperidine with a cyclohexyl group successfully attenuated hERG binding, but was accompanied by reduced in vivo efficacy. The approach of substituting a piperidine moiety with an oxazolidinone also attenuated hERG binding. Further refinement of this latter scaffold via SAR at the pyridine terminus and methyl branching on the oxazolidinone led to compounds 7e and 7f, which raised HDLc by 33 and 27mg/dl, respectively, in our transgenic mouse PD model and without the hERG liability of previous series.
Subject(s)
Benzoxazoles/chemistry , Cholesterol Ester Transfer Proteins/antagonists & inhibitors , Cholesterol, HDL/metabolism , Trans-Activators/metabolism , Animals , Benzoxazoles/chemical synthesis , Benzoxazoles/pharmacology , Inhibitory Concentration 50 , Mice , Mice, Transgenic , Molecular Structure , Protein Binding/drug effects , Structure-Activity Relationship , Transcriptional Regulator ERGABSTRACT
The development of 2-phenylbenzoxazoles as inhibitors of cholesteryl ester transfer protein (CETP) is described. Initial efforts aimed at engineering replacements for the aniline substructures in the benchmark molecule. Reversing the connectivity of the central aniline lead to a new class of 2-(4-carbonylphenyl)benzoxazoles. Structure-activity studies at the C-7 and terminal pyridine ring allowed for the optimization of potency and HDLc-raising efficacy in this new class of inhibitors. These efforts lead to the discovery of benzoxazole 11v, which raised HDLc by 24 mg/dl in our transgenic mouse PD model.
Subject(s)
Benzoxazoles/chemistry , Benzoxazoles/pharmacology , Cholesterol Ester Transfer Proteins/antagonists & inhibitors , Cholesterol, HDL/blood , Animals , Drug Design , Mice , Mice, Transgenic , Structure-Activity RelationshipABSTRACT
We describe structure-activity studies leading to the discovery of 2-arylbenzoxazole 3, the first in a series to raise serum high-density lipoprotein cholesterol levels in transgenic mice. Replacement of the 4-piperidinyloxy moiety with piperazinyl provided a more synthetically tractable lead, which upon optimization resulted in compound 4, an excellent inhibitor of cholesteryl ester transfer protein function with good pharmacokinetic properties and in vivo efficacy.
Subject(s)
Acetanilides/chemistry , Benzoxazoles/chemistry , Cholesterol Ester Transfer Proteins/antagonists & inhibitors , Cholesterol, HDL/blood , Acetanilides/chemical synthesis , Acetanilides/pharmacokinetics , Animals , Benzoxazoles/chemical synthesis , Benzoxazoles/pharmacokinetics , Cholesterol Ester Transfer Proteins/metabolism , Mice , Mice, Transgenic , Structure-Activity RelationshipABSTRACT
The development of a series of 2-arylbenzoxazole alpha-alkoxyamide and beta-alkoxyamine inhibitors of cholesteryl ester transfer protein (CETP) is described. Highly fluorinated alpha-alkoxyamides proved to be potent inhibitors of CETP in vitro, and the highly fluorinated 2-arylbenzoxazole beta-alkoxyamine 4 showed a desirable combination of in vitro potency (IC(50)=151 nM) and oral bioavailability in the mouse.
Subject(s)
Benzoxazoles/chemical synthesis , Benzoxazoles/metabolism , Cholesterol Ester Transfer Proteins/antagonists & inhibitors , Cholesterol Ester Transfer Proteins/metabolism , Alcohols/chemical synthesis , Alcohols/metabolism , Amides/chemical synthesis , Amides/metabolismABSTRACT
We have developed a family of 4-benzimidazolyl-N-piperazinethyl-pyrimidin-2-amines that are subnanomolar inhibitors of Lck. A subset of these Lck inhibitors, with heterocyclic substituents at the benzimidazole C5, are also low-nanomolar inhibitors of cellular IL2 release.
Subject(s)
Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/antagonists & inhibitors , Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/metabolism , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Pyrimidines/chemistry , Pyrimidines/pharmacology , Inhibitory Concentration 50 , Interleukin-2/antagonists & inhibitors , Interleukin-2/metabolism , Molecular Structure , Structure-Activity RelationshipABSTRACT
Epidemiological studies have demonstrated an inverse correlation between plasma concentrations of high-density lipoprotein cholesterol (HDL-C) and incidence of coronary heart disease (CHD); thus new therapies for raising HDL-C levels have been the focus of significant efforts by the cardiovascular medicine community. Inhibition of cholesteryl ester transfer protein (CETP) is one approach to increasing HDL-C concentrations. CETP is a plasma glycoprotein that mediates the transfer of cholesteryl esters from HDL to the apoB-containing lipoproteins, with a balanced transfer of triglycerides. Inhibition of CETP results in an accumulation of cholesteryl esters in HDL, thus resulting in increased HDL-C. Pharmacological inhibition of CETP in humans has been shown to result in increased levels of HDL-C, although any beneficial effect of this inhibition on CHD has yet to be established. This review article will discuss the complex role of CETP in lipid metabolism, recent developments for small-molecule inhibitors of CETP, and future prospects for CETP inhibitors in the treatment of CHD.
Subject(s)
Anticholesteremic Agents/therapeutic use , Atherosclerosis/drug therapy , Cholesterol Ester Transfer Proteins/antagonists & inhibitors , Cholesterol, HDL/blood , Animals , Anticholesteremic Agents/administration & dosage , Anticholesteremic Agents/chemistry , Anticholesteremic Agents/pharmacology , Atherosclerosis/blood , Atherosclerosis/epidemiology , Atherosclerosis/metabolism , Cholesterol Ester Transfer Proteins/physiology , Clinical Trials as Topic , Drug Design , Drug Evaluation, Preclinical , Humans , Lipid Metabolism/drug effects , Molecular StructureABSTRACT
Quinolinones and naphthyridinones with C7 N-t-butyl piperidine substituents were found to be potent p38 MAP kinase inhibitors. These compounds significantly suppress TNF-alpha release in both cellular and LPS-stimulated whole blood assays. They also displayed excellent PK profiles across three animal species. Quinolinone at 10 mpk showed comparable oral efficacy to that of dexamethasone at 1 mpk in a murine collagen-induced arthritis model.
Subject(s)
Enzyme Inhibitors/pharmacology , Naphthyridines/chemistry , Piperidines/chemistry , Quinolones/chemistry , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , Animals , Arthritis, Experimental , Collagen/chemistry , Dexamethasone/chemistry , Dogs , Haplorhini , Humans , Inhibitory Concentration 50 , Lipopolysaccharides/metabolism , Mice , Models, Chemical , Rats , Time Factors , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Tumor Necrosis Factor-alpha/chemistry , p38 Mitogen-Activated Protein Kinases/metabolismABSTRACT
We have synthesized a series of C7-piperidine- and 4-aminopiperidine-substituted naphthyridinones, quinolinones, and dihydroquinazolinones that are highly potent inhibitors of both p38MAP kinase activity and TNF-alpha release. The 4-aminopentamethylpiperidine naphthyridinone 5, which was designed to block metabolism at major 'hot spots', combined excellent inhibitory potency with good oral bioavailability in the rat.
