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1.
ACS Med Chem Lett ; 6(9): 987-92, 2015 Sep 10.
Article in English | MEDLINE | ID: mdl-26396685

ABSTRACT

In nonsmall cell lung cancer (NSCLC), the threonine(790)-methionine(790) (T790M) point mutation of EGFR kinase is one of the leading causes of acquired resistance to the first generation tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib. Herein, we describe the optimization of a series of 7-oxopyrido[2,3-d]pyrimidinyl-derived irreversible inhibitors of EGFR kinase. This led to the discovery of compound 24 which potently inhibits gefitinib-resistant EGFR(L858R,T790M) with 100-fold selectivity over wild-type EGFR. Compound 24 displays strong antiproliferative activity against the H1975 nonsmall cell lung cancer cell line, the first line mutant HCC827 cell line, and promising antitumor activity in an EGFR(L858R,T790M) driven H1975 xenograft model sparing the side effects associated with the inhibition of wild-type EGFR.

2.
Bioorg Med Chem Lett ; 23(23): 6396-400, 2013 Dec 01.
Article in English | MEDLINE | ID: mdl-24120542

ABSTRACT

A series of aminooxadiazoles was optimized for inhibition of Cdc7. Early lead isoquinoline 1 suffered from modest cell potency (cellular IC50=0.71 µM measuring pMCM2), low selectivity against structurally related kinases, and high IV clearance in rats (CL=18 L/h/kg). Extensive optimization resulted in azaindole 26 (Cdc7 IC50=1.1 nM, pMCM2 IC50=32 nM) that demonstrated robust lowering of pMCM2 in a mouse pharmacodynamic (PD) model when dosed orally. Modifications to improve the pharmacokinetic profile of this series were guided by trapping experiments with glutathione in rat hepatocytes.


Subject(s)
Cell Cycle Proteins/antagonists & inhibitors , Oxadiazoles/chemistry , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Animals , Cell Cycle Proteins/chemistry , Cell Cycle Proteins/metabolism , Disease Models, Animal , Female , Mice , Mice, Nude , Molecular Structure , Oxadiazoles/chemical synthesis , Oxadiazoles/pharmacology , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Protein Serine-Threonine Kinases/chemistry , Protein Serine-Threonine Kinases/metabolism , Rats , Structure-Activity Relationship , Xenograft Model Antitumor Assays
3.
Bioanalysis ; 4(1): 89-93, 2012 Jan.
Article in English | MEDLINE | ID: mdl-22191596

ABSTRACT

p38 MAP kinase is a key enzyme in the proinflammatory response and a large number of compounds have been studied as potential therapeutic drugs. This review summarizes the bioanalytical methods used for the analysis of p38 MAP kinase inhibitors, with a special focus on sample preparation and chromatographic analysis. Biological sample extraction techniques utilized included protein precipitation, liquid-liquid extraction and SPE. Applications include determinations of compounds in a variety of biological fluids and tissues. Extracted samples are typically separated by reverse-phase LC and quantitated either by UV or MS/MS detection. The benefits and limitations of each sample preparation strategy are discussed. The importance of chromatographic separation to avoid matrix effect and interference from endogenous compounds or drug-related biotransformation products are also discussed herein.


Subject(s)
Chromatography, Liquid/methods , Protein Kinase Inhibitors/pharmacology , Tandem Mass Spectrometry/methods , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , Animals , Blood Chemical Analysis/methods , Humans , Protein Kinase Inhibitors/blood , Protein Kinase Inhibitors/urine , Specimen Handling , Urinalysis/methods , p38 Mitogen-Activated Protein Kinases/blood , p38 Mitogen-Activated Protein Kinases/urine
4.
Bioorg Med Chem Lett ; 22(2): 1226-9, 2012 Jan 15.
Article in English | MEDLINE | ID: mdl-22196117

ABSTRACT

Structure-activity relationship (SAR) investigations of a novel class of triazolopyridazinone p38α mitogen activated protein kinase (MAPK) inhibitors are disclosed. From these studies, increased in vitro potency was observed for 2,6-disubstituted phenyl moieties and N-ethyl triazolopyridazinone cores due to key contacts with Leu108, Ala157 and Val38. Further investigation led to the identification of three compounds, 3g, 3j and 3m that are highly potent inhibitors of LPS-induced MAPKAP kinase 2 (MK2) phosphorylation in 50% human whole blood (hWB), and possess desirable in vivo pharmacokinetic and kinase selectivity profiles.


Subject(s)
Mitogen-Activated Protein Kinase 14/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Pyridazines/pharmacology , Triazoles/pharmacology , Crystallography, X-Ray , Dose-Response Relationship, Drug , Humans , Mitogen-Activated Protein Kinase 14/metabolism , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Pyridazines/chemical synthesis , Pyridazines/chemistry , Stereoisomerism , Structure-Activity Relationship , Triazoles/chemical synthesis , Triazoles/chemistry
5.
Drug Metab Dispos ; 39(9): 1668-73, 2011 Sep.
Article in English | MEDLINE | ID: mdl-21673127

ABSTRACT

The novel biotransformation of an aminopyrrolidine to an aminopiperidine during the metabolism of 5-(4-chlorophenyl)-3-methyl-2-((2R)-2-(((1-methylethyl)amino)methyl)-1-pyrrolidinyl)-6-(4-pyridinyl)-4(3H)-pyrimidinone (AMG657417) was investigated using the NADPH-fortified S9 fraction from human liver. The major metabolite (M18) had a protonated molecule (MH(+) m/z 438) identical to that of AMG657417 except that it eluted earlier on a reverse-phase high-performance liquid chromatography. The structure of M18 had been identified as 5-(4-chlorophenyl)-3-methyl-2-((1-(1-methylethyl)-3-piperidinyl)amino)-6-(4-pyridinyl)-4(3H)-pyrimidinone (I) by liquid chromatography-mass spectrometry and proton NMR. M18 was not observed when AMG657417 was incubated with either microsomal or cytosolic fraction from human liver, suggesting the involvement of both microsomal and cytosolic enzymes in the biotransformation. The reaction mechanisms have been elucidated by trapping the intermediates formed during the biotransformation. An aldehyde intermediate was initially produced by hydroxylation and opening of the pyrrolidine ring of the parent molecule, followed by intramolecular Schiff-base formation between the exocyclic isopropylamine nitrogen and the aldehyde carbonyl to form a piperidinyl iminium ion. The iminium ion was then reduced to the piperidine product. The presence of the aldehyde intermediate was verified by the formation of semicarbazide conjugates in human liver microsomal, S9, and recombinant CYP3A4 incubations of AMG657417. The presence of the piperidinyl iminium ion intermediate was confirmed by the formation of cyanide conjugates in the incubations in human liver S9. Two cyanide conjugates with identical protonated molecule and product ion mass spectra were observed, indicating the likelihood of diastereomer formation. A chemical inhibition study in NADPH-fortified S9 fraction indicated that the oxidation of AMG657417 was catalyzed almost exclusively by CYP3A.


Subject(s)
Cytochrome P-450 CYP3A/metabolism , Piperidines/pharmacokinetics , Pyrimidinones/pharmacokinetics , Pyrrolidines/pharmacokinetics , Biotransformation , Chromatography, High Pressure Liquid/methods , Humans , Hydroxylation , Ketoconazole/pharmacology , Magnetic Resonance Spectroscopy/methods , Mass Spectrometry/methods , Microsomes, Liver/enzymology , Microsomes, Liver/metabolism , Piperidines/metabolism , Pyrimidinones/metabolism , Pyrrolidines/metabolism , Semicarbazides/metabolism
6.
J Pharm Biomed Anal ; 55(5): 1104-10, 2011 Jul 15.
Article in English | MEDLINE | ID: mdl-21481559

ABSTRACT

A LC-MS/MS method was developed for the determination of a p38 MAP kinase inhibitor (Compound I) and its amide hydrolyzed metabolite (M7) in Cynomolgus monkey plasma over the concentration range of 1.00-1000ng/mL. Stable isotope labeled compounds (d(3)-Compound I and d(3)-M7) were used as internal standards (IS). Samples were prepared using protein precipitation in the 96-well format with a 30µL plasma sample volume. Chromatographic separation was performed with reversed-phase liquid chromatography on a Varian Monochrom C(18) (100mm×2.00mm, 5µm) analytical column. The mobile phases were 5mM ammonium formate in acetonitrile/water (95/5, v/v) pH 7.0 and 5mM ammonium formate in acetonitrile/water (5/95, v/v) pH 7.0. Gradient elution, at a flow rate of 550µL/min, was used to separate Compound I and M7. Positive atmospheric pressure chemical ionization was utilized with detection by multiple reaction monitoring (MRM). Total run time was about 3.2min. This method was validated following the current Food and Drug Administration (FDA) guidance for bioanalytical method validation. The intra- and inter-day precision (% CV) and accuracy (% bias) at all concentrations tested were below 15% for both analytes. The mean recoveries for Compound I, M7, d(3)-Compound I, and d(3)-M7 were 106%, 107%, 108% and 105%, respectively. The method was successfully applied to support a GLP toxicokinetic study in Cynomolgus monkeys after oral administration of Compound I. A total of 48 samples (∼12.5% of the total number of samples) were selected for incurred sample reanalysis (ISR). The % difference between the reassay concentrations and the original concentrations were all less than 20% of their mean values and met the acceptance criteria for ISR.


Subject(s)
Amides/chemistry , Enzyme Inhibitors/analysis , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , Acetonitriles/chemistry , Administration, Oral , Animals , Area Under Curve , Calibration , Chemistry Techniques, Analytical , Chromatography, Liquid/methods , Enzyme Inhibitors/blood , Female , Formates/chemistry , Ions , Macaca fascicularis , Male , Quality Control , Reproducibility of Results , Tandem Mass Spectrometry/methods , Water/chemistry
7.
J Med Chem ; 53(17): 6398-411, 2010 Sep 09.
Article in English | MEDLINE | ID: mdl-20712346

ABSTRACT

The p38 mitogen-activated protein kinase (MAPK) plays an important role in the production of proinflammatory cytokines, making it an attractive target for the treatment of various inflammatory diseases. A series of pyridazinopyridinone compounds were designed as novel p38 kinase inhibitors. A structure-activity investigation identified several compounds possessing excellent potency in both enzyme and human whole blood assays. Among them, compound 31 exhibited good pharmacokinetic properties and showed excellent selectivity against other related kinases. In addition, 31 demonstrated efficacy in a collagen-induced arthritis disease model in rats.


Subject(s)
Antirheumatic Agents/chemical synthesis , Pyridazines/chemical synthesis , Pyridones/chemical synthesis , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , Activating Transcription Factor 2/metabolism , Animals , Antirheumatic Agents/pharmacokinetics , Antirheumatic Agents/pharmacology , Arthritis, Experimental/chemically induced , Arthritis, Experimental/drug therapy , Binding Sites , Collagen , Female , Humans , Interleukin-8/biosynthesis , Interleukin-8/blood , Lipopolysaccharides/pharmacology , Male , Models, Molecular , Phosphorylation , Pyridazines/pharmacokinetics , Pyridazines/pharmacology , Pyridones/pharmacokinetics , Pyridones/pharmacology , Rats , Rats, Inbred Lew , Rats, Sprague-Dawley , Structure-Activity Relationship , Tumor Necrosis Factor-alpha/biosynthesis , Tumor Necrosis Factor-alpha/pharmacology
8.
J Med Chem ; 53(7): 2973-85, 2010 Apr 08.
Article in English | MEDLINE | ID: mdl-20218619

ABSTRACT

The p38alpha mitogen-activated protein (MAP) kinase is a central signaling molecule in many proinflammatory pathways, regulating the cellular response to a multitude of external stimuli including heat, ultraviolet radiation, osmotic shock, and a variety of cytokines especially interleukin-1beta and tumor necrosis factor alpha. Thus, inhibitors of this enzyme are postulated to have significant therapeutic potential for the treatment of rheumatoid arthritis, inflammatory bowel disease, and Crohn's disease, as well as other diseases where aberrant cytokine signaling is the driver of disease. In this communication, we describe a novel class of 7-alkyl-1,5-bis-aryl-pyrazolopyridinone-based p38alpha inhibitors. In particular, compound 3f is highly potent in the enzyme and cell-based assays, selective in an Ambit kinase screen, and efficacious (ED(50) < or = 0.01 mg/kg) in the rat collagen induced arthritis (CIA) model.


Subject(s)
Drug Discovery , Mitogen-Activated Protein Kinase 14/antagonists & inhibitors , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/pharmacology , Pyridones/administration & dosage , Pyridones/pharmacology , Administration, Oral , Animals , Arthritis/chemically induced , Arthritis/drug therapy , Collagen/pharmacology , Humans , Male , Mitogen-Activated Protein Kinase 14/chemistry , Models, Molecular , Molecular Conformation , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacokinetics , Pyridones/chemical synthesis , Pyridones/pharmacokinetics , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Substrate Specificity
9.
Bioorg Med Chem Lett ; 20(5): 1680-4, 2010 Mar 01.
Article in English | MEDLINE | ID: mdl-20138761

ABSTRACT

A novel class of pyrazolopyridazine p38alpha mitogen-activated protein kinase (MAPK) inhibitors is disclosed. A structure activity relationship (SAR) investigation was conducted driven by the ability of these compounds to inhibit the p38alpha enzyme, the secretion of TNFalpha in a LPS-challenged THP1 cell line and TNFalpha-induced production of IL-8 in the presence of 50% human whole blood (hWB). This study resulted in the discovery of several inhibitors with IC(50) values in the single-digit nanomolar range in hWB. Further investigation of the pharmacokinetic profiles of these lead compounds led to the identification of three potent and orally bioavailable p38alpha inhibitors 2h, 2m, and 13h. Inhibitor 2m was found to be highly selective for p38alpha/beta over a panel of 402 other kinases in Ambit screening, and was highly efficacious in vivo in the inhibition of TNFalpha production in LPS-stimulated Lewis rats with an ED(50) of ca. 0.08mg/kg.


Subject(s)
Anti-Inflammatory Agents/chemistry , Benzamides/chemistry , Protein Kinase Inhibitors/chemistry , Pyrazoles/chemistry , Pyridazines/chemistry , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , Administration, Oral , Animals , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/pharmacokinetics , Benzamides/chemical synthesis , Benzamides/pharmacokinetics , Binding Sites , Cell Line, Tumor , Crystallography, X-Ray , Humans , Interleukin-8 , Lipopolysaccharides/toxicity , Male , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacokinetics , Pyrazoles/chemical synthesis , Pyrazoles/pharmacokinetics , Pyridazines/chemical synthesis , Pyridazines/pharmacokinetics , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Tumor Necrosis Factor-alpha/metabolism , p38 Mitogen-Activated Protein Kinases/metabolism
10.
Bioorg Med Chem Lett ; 19(16): 4724-8, 2009 Aug 15.
Article in English | MEDLINE | ID: mdl-19574047

ABSTRACT

A novel class of fused pyrazole-derived inhibitors of p38alpha mitogen-activated protein kinase (MAPK) is disclosed. These inhibitors were evaluated for their ability to inhibit the p38alpha enzyme, the secretion of TNFalpha in a LPS-challenged THP1 cell line and TNFalpha-induced production of IL-8 in 50% human whole blood. This series was optimized through a SAR investigation to provide inhibitors with IC(50) values in the low single-digit nanomolar range in whole blood. Further investigation of their pharmacokinetic profiles led to the identification of two potent and orally bioavailable p38 inhibitors 10 m and 10 q. Inhibitor 10 m was found to be efficacious in vivo in the inhibition of TNFalpha production in LPS-stimulated Lewis rats with an ED(50) of 0.1mg/kg while 10 q was found to have an ED(50) of 0.05-0.07 mg/kg.


Subject(s)
Anti-Inflammatory Agents/chemistry , Mitogen-Activated Protein Kinase 14/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Pyrazoles/chemistry , Pyridones/chemistry , Administration, Oral , Animals , Anti-Inflammatory Agents/administration & dosage , Anti-Inflammatory Agents/pharmacokinetics , Binding Sites , Cell Line , Computer Simulation , Crystallography, X-Ray , Humans , Interleukin-8/blood , Lipopolysaccharides/pharmacology , Male , Mitogen-Activated Protein Kinase 14/metabolism , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/pharmacokinetics , Pyrazoles/administration & dosage , Pyrazoles/pharmacokinetics , Pyridones/administration & dosage , Pyridones/pharmacokinetics , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Tumor Necrosis Factor-alpha/metabolism
11.
J Med Chem ; 51(20): 6280-92, 2008 Oct 23.
Article in English | MEDLINE | ID: mdl-18817364

ABSTRACT

The p38 mitogen-activated protein kinase (MAPK) is a central signaling molecule in many proinflammatory pathways, regulating the cellular response to a multitude of external stimuli including heat, ultraviolet radiation, osmotic shock, and a variety of cytokines especially interleukin-1beta and tumor necrosis factor alpha. Thus, inhibitors of this enzyme are postulated to have significant therapeutic potential for the treatment of rheumatoid arthritis, inflammatory bowel disease, osteoporosis, and many other diseases where aberrant cytokine signaling is the driver of disease. Herein, we describe a novel class of 3-amino-7-phthalazinylbenzoisoxazole-based inhibitors. With relatively low molecular weight, these compounds are highly potent in enzyme and cell-based assays, with minimal protein shift in 50% human whole blood. Compound 3c was efficacious (ED 50 = 0.05 mg/kg) in the rat collagen induced arthritis (CIA) model.


Subject(s)
Amines/chemistry , Benzene/chemistry , Isoxazoles/administration & dosage , Isoxazoles/pharmacology , Mitogen-Activated Protein Kinase 14/antagonists & inhibitors , Phthalazines/chemistry , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/pharmacology , Administration, Oral , Animals , Arthritis/chemically induced , Arthritis/drug therapy , Arthritis/enzymology , Crystallography, X-Ray , Disease Models, Animal , Humans , Isoxazoles/chemistry , Isoxazoles/therapeutic use , Mitogen-Activated Protein Kinase 14/chemistry , Mitogen-Activated Protein Kinase 14/metabolism , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Rats , Structure-Activity Relationship
12.
J Med Chem ; 51(20): 6271-9, 2008 Oct 23.
Article in English | MEDLINE | ID: mdl-18817365

ABSTRACT

Investigations into the structure-activity relationships (SAR) of a series of phthalazine-based inhibitors of p38 are described. These efforts originated from quinazoline 1 and through rational design led to the development of a series of orally bioavailable, potent, and selective inhibitors. Kinase selectivity was achieved by exploiting a collection of interactions with p38alpha including close contact to Ala157, occupation of the hydrophobic gatekeeper pocket, and a residue flip with Gly110. Substitutions on the phthalazine influenced the pharmacokinetic properties, of which compound 16 displayed the most desirable profile. Oral dosing (0.03 mg/kg) of 16 in rats 1 h prior to LPS challenge gave a >50% decrease in TNFalpha production.


Subject(s)
Mitogen-Activated Protein Kinase 14/antagonists & inhibitors , Phthalazines/chemistry , Phthalazines/pharmacology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Animals , Cells, Cultured , Crystallography, X-Ray , Drug Evaluation, Preclinical , Humans , Mitogen-Activated Protein Kinase 14/chemistry , Mitogen-Activated Protein Kinase 14/metabolism , Models, Molecular , Molecular Structure , Phthalazines/chemical synthesis , Protein Kinase Inhibitors/chemical synthesis , Quinolines/chemical synthesis , Quinolines/chemistry , Quinolines/pharmacology , Rats , Sensitivity and Specificity , Structure-Activity Relationship
13.
J Med Chem ; 51(6): 1681-94, 2008 Mar 27.
Article in English | MEDLINE | ID: mdl-18321037

ABSTRACT

The lymphocyte-specific kinase (Lck), a member of the Src family of cytoplasmic tyrosine kinases, is expressed in T cells and natural killer (NK) cells. Genetic evidence, including knockout mice and human mutations, demonstrates that Lck kinase activity is critical for normal T cell development, activation, and signaling. Selective inhibition of Lck is expected to offer a new therapy for the treatment of T-cell-mediated autoimmune and inflammatory disease. With the aid of X-ray structure-based analysis, aminopyrimidine amides 2 and 3 were designed from aminoquinazolines 1, which had previously been demonstrated to exhibit potent inhibition of Lck and T cell proliferation. In this report, we describe the synthesis and structure-activity relationships of a series of novel aminopyrimidine amides 3 possessing improved cellular potency and selectivity profiles relative to their aminoquinazoline predecessors 1. Orally bioavailable compound 13b inhibited the anti-CD3-induced production of interleukin-2 (IL-2) in mice in a dose-dependent manner (ED 50 = 9.4 mg/kg).


Subject(s)
Amides/pharmacology , Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Pyrimidines/pharmacology , T-Lymphocytes/drug effects , Administration, Oral , Amides/chemical synthesis , Amides/chemistry , Animals , Cell Proliferation/drug effects , Crystallography, X-Ray , Dose-Response Relationship, Drug , Drug Design , Enzyme Activation/drug effects , Female , Humans , Interleukin-2/antagonists & inhibitors , Interleukin-2/metabolism , Killer Cells, Natural/drug effects , Killer Cells, Natural/metabolism , Lipopolysaccharides/pharmacology , Male , Mice , Mice, Inbred BALB C , Mice, Knockout , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Rats , Rats, Sprague-Dawley , Signal Transduction/drug effects , Signal Transduction/physiology , Stereoisomerism , Structure-Activity Relationship , T-Lymphocytes/metabolism
14.
J Med Chem ; 51(6): 1637-48, 2008 Mar 27.
Article in English | MEDLINE | ID: mdl-18278858

ABSTRACT

Lck, or lymphocyte specific kinase, is a cytoplasmic tyrosine kinase of the Src family expressed in T-cells and NK cells. Genetic evidence from knockout mice and human mutations demonstrates that Lck kinase activity is critical for T-cell receptor-mediated signaling, leading to normal T-cell development and activation. A small molecule inhibitor of Lck is expected to be useful in the treatment of T-cell-mediated autoimmune and inflammatory disorders and/or organ transplant rejection. In this paper, we describe the structure-guided design, synthesis, structure-activity relationships, and pharmacological characterization of 2-amino-6-phenylpyrimido[5',4':5,6]pyrimido[1,2- a]benzimidazol-5(6 H)-ones, a new class of compounds that are potent inhibitors of Lck. The most promising compound of this series, 6-(2,6-dimethylphenyl)-2-((4-(4-methyl-1-piperazinyl)phenyl)amino)pyrimido[5',4':5,6]pyrimido-[1,2- a]benzimidazol-5(6 H)-one ( 25), exhibits potent inhibition of Lck kinase activity. This activity translates into inhibition of in vitro cell-based assays and in vivo models of T-cell activation and arthritis, respectively.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Arthritis/drug therapy , Benzimidazoles/chemical synthesis , Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/antagonists & inhibitors , Protein Kinase Inhibitors/chemical synthesis , Pyrimidinones/chemical synthesis , Administration, Oral , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Benzimidazoles/chemistry , Benzimidazoles/pharmacology , Crystallography, X-Ray , Disease Models, Animal , Drug Design , Drug Evaluation, Preclinical , Enzyme Activation/drug effects , Female , Injections, Intradermal , Interleukin-2/metabolism , Male , Mice , Mice, Inbred BALB C , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Pyrimidinones/chemistry , Pyrimidinones/pharmacology , Rats , Rats, Inbred Lew , Rats, Sprague-Dawley , Reproducibility of Results , Stereoisomerism , Structure-Activity Relationship , T-Lymphocytes/drug effects , T-Lymphocytes/metabolism
17.
J Med Chem ; 49(19): 5671-86, 2006 Sep 21.
Article in English | MEDLINE | ID: mdl-16970394

ABSTRACT

The lymphocyte-specific kinase (Lck) is a cytoplasmic tyrosine kinase of the Src family expressed in T cells and natural killer (NK) cells. Genetic evidence in both mice and humans demonstrates that Lck kinase activity is critical for signaling mediated by the T cell receptor (TCR), which leads to normal T cell development and activation. Selective inhibition of Lck is expected to offer a new therapy for the treatment of T-cell-mediated autoimmune and inflammatory disease. Screening of our kinase-preferred collection identified aminoquinazoline 1 as a potent, nonselective inhibitor of Lck and T cell proliferation. In this report, we describe the synthesis and structure-activity relationships of a series of novel aminoquinazolines possessing in vitro mechanism-based potency. Optimized, orally bioavailable compounds 32 and 47 exhibit anti-inflammatory activity (ED(50) of 22 and 11 mg/kg, respectively) in the anti-CD3-induced production of interleukin-2 (IL-2) in mice.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Benzamides/chemical synthesis , Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/antagonists & inhibitors , Quinazolines/chemical synthesis , Administration, Oral , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Benzamides/chemistry , Benzamides/pharmacology , Biological Availability , Cell Proliferation/drug effects , Cells, Cultured , Female , Humans , In Vitro Techniques , Interleukin-2/biosynthesis , Male , Mice , Mice, Inbred BALB C , Models, Molecular , Quinazolines/chemistry , Quinazolines/pharmacology , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , T-Lymphocytes/cytology , T-Lymphocytes/drug effects , T-Lymphocytes/immunology , Tumor Necrosis Factor-alpha/biosynthesis
18.
J Med Chem ; 49(16): 4981-91, 2006 Aug 10.
Article in English | MEDLINE | ID: mdl-16884310

ABSTRACT

The lymphocyte-specific kinase (Lck) is a cytoplasmic tyrosine kinase of the Src family expressed in T cells and NK cells. Genetic evidence in both mice and humans demonstrates that Lck kinase activity is critical for signaling mediated by the T cell receptor (TCR), which leads to normal T cell development and activation. A small molecule inhibitor of Lck is expected to be useful in the treatment of T cell-mediated autoimmune and inflammatory disorders and/or organ transplant rejection. In this paper, we describe the synthesis, structure-activity relationships, and pharmacological characterization of 2-aminopyrimidine carbamates, a new class of compounds with potent and selective inhibition of Lck. The most promising compound of this series, 2,6-dimethylphenyl 2-((3,5-bis(methyloxy)-4-((3-(4-methyl-1-piperazinyl)propyl)oxy)phenyl)amino)-4-pyrimidinyl(2,4-bis(methyloxy)phenyl)carbamate (43) exhibits good activity when evaluated in in vitro assays and in an in vivo model of T cell activation.


Subject(s)
Aminopyridines/chemical synthesis , Anti-Inflammatory Agents/chemical synthesis , Carbamates/chemical synthesis , Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/antagonists & inhibitors , Pyrimidines/chemical synthesis , Administration, Oral , Aminopyridines/chemistry , Aminopyridines/pharmacology , Animals , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacology , Biological Availability , Carbamates/chemistry , Carbamates/pharmacology , Crystallography, X-Ray , Humans , In Vitro Techniques , Jurkat Cells , Lymphocyte Activation , Lymphocyte Culture Test, Mixed , Mice , Mice, Inbred BALB C , Models, Molecular , Molecular Structure , Pyrimidines/chemistry , Pyrimidines/pharmacology , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , T-Lymphocytes/drug effects , T-Lymphocytes/immunology
19.
Bioorg Med Chem Lett ; 16(19): 5066-72, 2006 Oct 01.
Article in English | MEDLINE | ID: mdl-16887348

ABSTRACT

Melanin-concentrating hormone (MCH) is a cyclic 19 amino acid orexigenic neuropeptide. The action of MCH on feeding is thought to involve the activation of its respective G protein-coupled receptor MCH-R1. Consequently, antagonists that block MCH regulated MCH-R1 activity may provide a viable approach to the treatment of diet-induced obesity. This communication reports the discovery of a novel MCH-R1 receptor antagonist, the biarylether 7, identified through high throughput screening. The solid-phase synthesis and structure-activity relationship of related analogs is described.


Subject(s)
Ethers/chemical synthesis , Receptors, Pituitary Hormone/antagonists & inhibitors , Receptors, Somatostatin/antagonists & inhibitors , Combinatorial Chemistry Techniques , Drug Evaluation, Preclinical , Ethers/pharmacology , Humans , Inhibitory Concentration 50 , Obesity/drug therapy , Structure-Activity Relationship
20.
Drug Metab Dispos ; 32(12): 1377-82, 2004 Dec.
Article in English | MEDLINE | ID: mdl-15333514

ABSTRACT

The dietary polyphenol resveratrol has been shown to have chemopreventive activity against cardiovascular disease and a variety of cancers in model systems, but it is not clear whether the drug reaches the proposed sites of action in vivo after oral ingestion, especially in humans. In this study, we examined the absorption, bioavailability, and metabolism of 14C-resveratrol after oral and i.v. doses in six human volunteers. The absorption of a dietary relevant 25-mg oral dose was at least 70%, with peak plasma levels of resveratrol and metabolites of 491 +/- 90 ng/ml (about 2 microM) and a plasma half-life of 9.2 +/- 0.6 h. However, only trace amounts of unchanged resveratrol (<5 ng/ml) could be detected in plasma. Most of the oral dose was recovered in urine, and liquid chromatography/mass spectrometry analysis identified three metabolic pathways, i.e., sulfate and glucuronic acid conjugation of the phenolic groups and, interestingly, hydrogenation of the aliphatic double bond, the latter likely produced by the intestinal microflora. Extremely rapid sulfate conjugation by the intestine/liver appears to be the rate-limiting step in resveratrol's bioavailability. Although the systemic bioavailability of resveratrol is very low, accumulation of resveratrol in epithelial cells along the aerodigestive tract and potentially active resveratrol metabolites may still produce cancer-preventive and other effects.


Subject(s)
Antineoplastic Agents, Phytogenic/pharmacokinetics , Stilbenes/pharmacokinetics , Administration, Oral , Adult , Antineoplastic Agents, Phytogenic/administration & dosage , Biological Availability , Biotransformation , Chromatography, High Pressure Liquid , Feces/chemistry , Female , Half-Life , Humans , Injections, Intravenous , Intestinal Absorption , Male , Mass Spectrometry , Resveratrol , Stilbenes/administration & dosage , Sulfates/metabolism
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