ABSTRACT
Lysophosphatidic acid (LPA) is a bioactive lipid mediator that elicits a number of biological functions, including smooth muscle contraction, cell motility, proliferation, and morphological change. LPA is endogenously produced by autotaxin (ATX) from extracellular lysophosphatidylcholine (LPC) in plasma. Herein, we report our medicinal chemistry effort to identify a novel and highly potent ATX inhibitor, ONO-8430506 (20), with good oral availability. To enhance the enzymatic ATX inhibitory activity, we designed several compounds by structurally comparing our hit compound with the endogenous ligand LPC. Further optimization to improve the pharmacokinetic profile and enhance the ATX inhibitory activity in human plasma resulted in the identification of ONO-8430506 (20), which enhanced the antitumor effect of paclitaxel in a breast cancer model.
ABSTRACT
An orally active dual CysLT1 and CysLT2 antagonist possessing a distinctive structure which consists of triple bond and dicarboxylic acid moieties is described. Gemilukast (ONO-6950) was generated via isomerization of the core indole and the incorporation of a triple bond into a lead compound. Gemilukast exhibited antagonist activities with IC50 values of 1.7 and 25 nM against human CysLT1 and human CysLT2, respectively, and potent efficacy at an oral dose of 0.1 mg/kg given 24 h before LTD4 challenge in a CysLT1-dependent guinea pig asthmatic model. In addition, gemilukast dose-dependently reduced LTC4-induced bronchoconstriction in both CysLT1- and CysLT2-dependent guinea pig asthmatic models, and it reduced antigen-induced constriction of isolated human bronchi. Gemilukast is currently being evaluated in phase II trials for the treatment of asthma.
Subject(s)
Asthma/drug therapy , Butyrates/pharmacology , Butyrates/therapeutic use , Indoles/pharmacology , Indoles/therapeutic use , Leukotriene Antagonists/pharmacology , Leukotriene Antagonists/therapeutic use , Receptors, Leukotriene/drug effects , Animals , Biological Availability , Dogs , Guinea Pigs , Humans , Leukotriene Antagonists/pharmacokinetics , RatsABSTRACT
Based on the original spirodiketopiperazine design framework, further optimization of an orally available CCR5 antagonist was undertaken. Structural hybridization of the hydroxylated analog 4 derived from one of the oxidative metabolites and the new orally available non-hydroxylated benzoic acid analog 5 resulted in another potent orally available CCR5 antagonist 6a as a clinical candidate. Full details of a structure-activity relationship (SAR) study and ADME properties are presented.
Subject(s)
Anti-HIV Agents/chemistry , Benzoates/chemistry , CCR5 Receptor Antagonists , Diketopiperazines/chemistry , Administration, Oral , Animals , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/pharmacokinetics , Benzoates/chemical synthesis , Benzoates/pharmacokinetics , Diketopiperazines/chemical synthesis , Diketopiperazines/pharmacokinetics , Dogs , Drug Evaluation, Preclinical , Guinea Pigs , Haplorhini , Humans , Rabbits , Rats , Receptors, CCR5/metabolism , Structure-Activity RelationshipABSTRACT
Following the discovery that hydroxylated derivative 3 (Fig. 1) was one of the oxidative metabolites of the original lead 1, it was found that hydroxylated compound 4 possesses higher in vitro anti-HIV potency than the corresponding non-hydroxylated compound 2. Structural hybridation of 4 with the orally available analog 5 resulted in another orally-available spirodiketopiperazine CCR5 antagonist 6a that possesses more favorable pharmaceutical profile for use as a drug candidate.
Subject(s)
Anti-HIV Agents/chemistry , CCR5 Receptor Antagonists , Diketopiperazines/chemistry , Spiro Compounds/chemistry , Administration, Oral , Animals , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/pharmacokinetics , Cell Line, Tumor , Diketopiperazines/chemical synthesis , Diketopiperazines/pharmacokinetics , Diketopiperazines/pharmacology , Drug Evaluation, Preclinical , HIV Core Protein p24/metabolism , HIV-1/metabolism , Humans , Microsomes, Liver/metabolism , Rats , Receptors, CCR5/metabolism , Spiro Compounds/chemical synthesis , Spiro Compounds/pharmacology , StereoisomerismABSTRACT
Using the previously reported novel spirodiketopiperazine scaffold, the design and synthesis of orally available CCR5 antagonists was undertaken. Compounds possessing a carboxylic acid function in the appropriate position showed improved oral exposure (AUC) relative to the initial chemical leads without reduction in the antagonist activity. The optimized compound 40 was found to show potent anti-HIV activity. Full details of structure-activity relationship (SAR) study are presented.
Subject(s)
Anti-HIV Agents/pharmacology , Anti-HIV Agents/pharmacokinetics , CCR5 Receptor Antagonists , HIV Infections/drug therapy , HIV-1/drug effects , Piperazines/pharmacology , Piperazines/pharmacokinetics , Administration, Oral , Animals , Anti-HIV Agents/chemistry , Biological Availability , Caco-2 Cells , Humans , Piperazines/chemistry , Rats , Receptors, CCR5/metabolismABSTRACT
Spirodiketopiperazine-based CCR5 antagonists, showing improved pharmacokinetic profiles without reduction in antagonist activity, were designed and synthesized. We also demonstrate the anti-HIV activity of a representative compound 12, as measured in a p24 assay.
Subject(s)
Anti-HIV Agents/pharmacokinetics , CCR5 Receptor Antagonists , Piperazines/pharmacokinetics , Animals , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/chemistry , HIV Core Protein p24/metabolism , Humans , Microsomes, Liver/metabolism , Piperazines/chemical synthesis , Piperazines/chemistry , Rats , Receptors, CCR5/metabolismABSTRACT
Hydroxylated derivatives were designed and synthesized based on the information of oxidative metabolites. Compounds derived from beta-substituted (2R,3R)-2-amino-3-hydroxypropionic acid showed improved inhibitory activities against the binding of MIP-1alpha to human CCR5, compared with the non-hydroxylated derivatives and the other isomers.
Subject(s)
Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/pharmacology , CCR5 Receptor Antagonists , Animals , CHO Cells , Chemokine CCL3 , Chemokine CCL4 , Chromatography, High Pressure Liquid , Combinatorial Chemistry Techniques , Cricetinae , Cricetulus , Drug Design , Humans , Hydroxylation , In Vitro Techniques , Indicators and Reagents , Isomerism , Macrophage Inflammatory Proteins/metabolism , Magnetic Resonance Spectroscopy , Microsomes, Liver/enzymology , Microsomes, Liver/metabolism , Oxidation-Reduction , Protein Binding , RatsABSTRACT
A series of 2-iminopiperidines fused to small-membered rings (Tables 1 and 2) were synthesised and biologically evaluated using an in vitro human nitric oxide synthase (NOS) inhibition assay. Fused bicyclic compounds 5-9 exhibited nearly the same potency as compound 1 in the hiNOS inhibition assay. Among these, the 1-methyl analogues 8 and 9 showed better isoform selectivity than their corresponding unsubstituted analogues 7 and 6, respectively. Compounds 5 and 6 were also evaluated by an in vivo NO accumulation assay in a mouse model. The discovery process of new chemical leads for an orally bioavailable inhibitor of human inducible NOS (iNOS) is reported. The structure-activity relationship (SAR) study and chemistry of these compounds are also reported.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Nitric Oxide Synthase/antagonists & inhibitors , Piperidines/chemical synthesis , Piperidines/pharmacology , Administration, Oral , Animals , Biological Availability , Drug Design , Enzyme Inhibitors/toxicity , Humans , Indicators and Reagents , Isoenzymes/antagonists & inhibitors , Kinetics , Mice , Mice, Inbred BALB C , Nitric Oxide Synthase Type II , Recombinant Proteins/drug effects , Structure-Activity Relationship , Substrate Specificity , omega-N-Methylarginine/pharmacologyABSTRACT
Further chemical modification of 2-iminopiperidines fused to cyclopropane rings was performed. Optically active isomers 2 and 13 were synthesized and their biological activity was evaluated. Compound 2 exhibited greater potency and more isoform selectivity than enantiomer 13 in the iNOS inhibition assay. One of the gem-chlorines on the fused cyclopropane moiety of 2 was eliminated to produce 3, which showed reduced potency for iNOS inhibition, as well as 4 with an increased potency. The isoform selectivity of 4 was also much higher than that of 3. This was also true for the corresponding methyl derivatives 6-9. The structure-activity relationship (SAR) study and computer aided docking study of the most optimized structure 4 with human iNOS will also be reported.
Subject(s)
Bridged Bicyclo Compounds/chemical synthesis , Bridged Bicyclo Compounds/pharmacology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Imines/chemical synthesis , Imines/pharmacology , Nitric Oxide Synthase/antagonists & inhibitors , Animals , Biological Availability , Bridged Bicyclo Compounds/chemistry , Bridged Bicyclo Compounds/toxicity , Crystallography, X-Ray , Cyclopropanes/chemical synthesis , Cyclopropanes/chemistry , Cyclopropanes/pharmacology , Drug Design , Enzyme Inhibitors/toxicity , Humans , Imines/chemistry , Imines/toxicity , Inhibitory Concentration 50 , Magnetic Resonance Spectroscopy , Mice , Mice, Inbred BALB C , Nitric Oxide Synthase/genetics , Nitric Oxide Synthase Type II , Piperidines/chemical synthesis , Piperidines/chemistry , Piperidines/pharmacology , Recombinant Proteins/antagonists & inhibitors , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Structure-Activity Relationship , omega-N-Methylarginine/pharmacologyABSTRACT
The process of discovery and biological evaluation of alpha,beta-unsaturated cyclic amidines, as selective inhibitors of inducible nitric oxide synthase (iNOS), is reported. Dihydropyridin-2(1H)-imines and 1,5,6,7-tetrahydro-2H-azepin-2-imines were synthesized and biologically evaluated both in vitro and in vivo using a nitric oxide synthase inhibition assay. Compounds 1, 5, 6, 8-12 and 16 exhibited potent inhibition of iNOS. Among these, compounds 6, 7, 10, 11 and 16 showed 5- to 19-fold isoform selectivity. Compounds 1, 6, 10, 11 and 16 also showed potent inhibitory activity in the NOx accumulation assay in mice. Compounds 1 and 6 showed excellent bioavailability (BA) in rats when administered orally. Full details are presented here, including the structure-activity relationship (SAR) studies, the chemistry of these compounds, and the pharmacokinetic data and the computer-aided docking study of 10 with hiNOS.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Imines/chemical synthesis , Imines/pharmacology , Nitric Oxide Synthase/antagonists & inhibitors , Pyridines/chemical synthesis , Pyridines/pharmacology , Animals , Biological Availability , Computer Simulation , Drug Design , Enzyme Inhibitors/pharmacokinetics , Indicators and Reagents , Injections, Intravenous , Isoenzymes/antagonists & inhibitors , Kinetics , Mass Spectrometry , Mice , Models, Molecular , Molecular Conformation , Nitrates/metabolism , Nitric Oxide Synthase Type II , Rats , Recombinant Proteins/chemistry , Structure-Activity RelationshipABSTRACT
Dihydropyridin-2-imines were synthesized and biologically evaluated both in vitro and in vivo using a nitric oxide inhibition assay. Compounds 1, 4, 5 and 7-11 exhibited potent activity in the inducible nitric oxide (iNOS) inhibition assay. Of these 5, 6, 9 and 10 showed 5- to 11-fold increases in isoform selectivity. Compounds 1, 5, 9 and 10 showed potent inhibitory activity in the NOx accumulation assay in mice. Compounds 1 and 5 also showed good bioavailability (BA) when given orally.
