Sources of food affect dietary adequacy of Inuit women of childbearing age in Arctic Canada.

Dietary transition in the Arctic is associated with decreased quality of diet, which is of particular concern for women of childbearing age due to the potential impact of maternal nutrition status on the next generation. The study assessed dietary intake and adequacy among Inuit women of childbearing age living in three communities in Nunavut, Canada. A culturally-appropriate quantitative food-frequency questionnaire was administered to 106 Inuit women aged 19-44 years.

Utilization of a nitrogen-sulfur nonbonding interaction in the design of new 2-aminothiazol-5-yl-pyrimidines as p38α MAP kinase inhibitors.

The design, synthesis, and structure-activity relationships (SAR) of a series of 2-aminothiazol-5-yl-pyrimidines as novel p38α MAP kinase inhibitors are described. These efforts led to the identification of 41 as a potent p38α inhibitor that utilizes a unique nitrogen-sulfur intramolecular nonbonding interaction to stabilize the conformation required for binding to the p38α active site. X-ray crystallographic studies that confirm the proposed binding mode of this class of inhibitors in p38 α and provide evidence for the proposed intramolecular nitrogen-sulfur interaction are discussed.

Extracellular signal-regulated kinase-dependent interstitial macrophage proliferation in the obstructed mouse kidney.

Aim: A number of growth factors have been shown to induce proliferation of renal cell types in animal models of kidney disease. In vitro studies suggest that many such growth factors induce renal cell proliferation through the extracellular signal-regulated kinase (ERK) pathway. The aim of this study was to determine the functional role of ERK signalling in cell proliferation in the obstructed kidney.

Benzothiazole based inhibitors of p38alpha MAP kinase.

Rational design, synthesis, and SAR studies of a novel class of benzothiazole based inhibitors of p38alpha MAP kinase are described. The issue of metabolic instability associated with vicinal phenyl, benzo[d]thiazol-6-yl oxazoles/imidazoles was addressed by the replacement of the central oxazole or imidazole ring with an aminopyrazole system. The proposed binding mode of this new class of p38alpha inhibitors was confirmed by X-ray crystallographic studies of a representative inhibitor (6a) bound to the p38alpha enzyme.

Potent, selective, orally bioavailable inhibitors of tumor necrosis factor-alpha converting enzyme (TACE): discovery of indole, benzofuran, imidazopyridine and pyrazolopyridine P1' substituents.

Potent and selective inhibitors of tumor necrosis factor-alpha converting enzyme (TACE) were discovered with several new heterocyclic P1' groups in conjunction with cyclic beta-amino hydroxamic acid scaffolds. Among them, the pyrazolopyridine provided the best overall profile when combined with tetrahydropyran beta-amino hydroxamic acid scaffold. Specifically, inhibitor 49 showed IC(50) value of 1 nM against porcine TACE and 170 nM in the suppression of LPS-induced TNF-alpha of human whole blood.

Potent, exceptionally selective, orally bioavailable inhibitors of TNF-alpha Converting Enzyme (TACE): novel 2-substituted-1H-benzo[d]imidazol-1-yl)methyl)benzamide P1' substituents.

Novel ((2-substituted-1H-benzo[d]imidazol-1-yl)methyl)benzamides were found to be excellent P1' substituents in conjunction with unique constrained beta-amino hydroxamic acid scaffolds for the discovery of potent selective inhibitors of TNF-alpha Converting Enzyme (TACE). Optimized examples proved potent for TACE, exceptionally selective over a wide panel of MMP and ADAM proteases, potent in the suppression of LPS-induced TNF-alpha in human whole blood and orally bioavailable.

Alpha,Beta-cyclic-beta-benzamido hydroxamic acids: Novel oxaspiro[4.4]nonane templates for the discovery of potent, selective, orally bioavailable inhibitors of tumor necrosis factor-alpha converting enzyme (TACE).

Two novel oxaspiro[4.4]nonane beta-benzamido hydroxamic scaffolds have been synthesized in enantio- and diasteriomerically pure form. These templates proved to be exceptional platforms that have led to the discovery of potent inhibitors of TACE that are active in a cellular assay measuring suppression of LPS-induced TNF-alpha.

Discovery of beta-benzamido hydroxamic acids as potent, selective, and orally bioavailable TACE inhibitors.

Beta-benzamido hydroxamic acids were discovered as potent TACE inhibitors. A computer model was constructed to help understanding the binding activities and guiding SAR study. SAR optimization led to the discovery of compound 30 which met all in vitro and in vivo criteria for the program and was selected for further evaluation.

The map kinase ERK regulates renal activity of cyclin-dependent kinase 2 in experimental glomerulonephritis.

Background: In vitro, the extracellular signal-regulated kinase (ERK) is an intracellular convergence point of multiple stimuli, which affect the cell cycle. However, the role of ERK in cell cycle regulation in vivo is unknown.

Methods: To address this issue, ERK activity was blocked both in vitro in mesangial cells (MC) and in vivo in experimental glomerulonephritis (GN) by a pharmacological inhibitor (U0126) of the ERK-activating kinase.

Pharmacokinetics and pharmacodynamics of DPC 333 ((2R)-2-((3R)-3-amino-3{4-[2-methyl-4-quinolinyl) methoxy] phenyl}-2-oxopyrrolidinyl)-N-hydroxy-4-methylpentanamide)), a potent and selective inhibitor of tumor necrosis factor alpha-converting enzyme in rodents, dogs, chimpanzees, and humans.

DPC 333 ((2R)-2-((3R)-3-amino-3{4-[2-methyl-4-quinolinyl) methoxy] phenyl}-2-oxopyrrolidinyl)-N-hydroxy-4-methylpentanamide)) is a potent and selective inhibitor of tumor necrosis factor (TNF)-alpha-converting enzyme (TACE). It significantly inhibits lipopolysaccharide-induced soluble TNF-alpha production in blood from rodents, chimpanzee, and human, with IC(50) values ranging from 17 to 100 nM. In rodent models of endotoxemia, DPC 333 inhibited the production of TNF-alpha in a dose-dependent manner, with an oral ED(50) ranging from 1.

Discovery of a small molecule antagonist of the parathyroid hormone receptor by using an N-terminal parathyroid hormone peptide probe.

Once-daily s.c. administration of either human parathyroid hormone (PTH)-(1-84) or recombinant human PTH-(1-34) provides for dramatic increases in bone mass in women with postmenopausal osteoporosis.

A new 4-(2-methylquinolin-4-ylmethyl)phenyl P1' group for the beta-amino hydroxamic acid derived TACE inhibitors.

A new P1' group for TACE inhibitors was identified by eliminating the oxygen atom in the linker of the original 4-(2-methylquinolin-4-ylmethoxy)phenyl P1' group. Incorporation of this 4-(2-methylquinolin-4-ylmethyl)phenyl group onto different beta-aminohydroxamic acid cores provided compound 18, which demonstrated potent porcine TACE (p-TACE) and human whole blood activity, excellent PK properties, and good selectivity against a variety of MMPs.

Selective inhibition of eosinophil influx into the lung by small molecule CC chemokine receptor 3 antagonists in mouse models of allergic inflammation.

CC chemokine receptor (CCR) 3 is a chemokine receptor implicated in recruiting cells, particularly eosinophils (EPhi), to the lung in episodes of allergic asthma. To investigate the efficacy of selective, small molecule antagonists of CCR3, we developed a murine model of EPhi recruitment to the lung. Murine eotaxin was delivered intranasally to mice that had previously received i.

Synthesis and structure-activity relationship of a novel, achiral series of TNF-alpha converting enzyme inhibitors.

A novel series of achiral TNF-alpha converting enzyme (TACE) inhibitors has been discovered. These compounds exhibited activities from 0.35 to 11nM in a porcine TACE assay and inhibited TNF-alpha production in an LPS-stimulated whole blood assay with an IC(50) value of 23nM for the most potent one.

Role of the ERK pathway in psychostimulant-induced locomotor sensitization.

Background: Repeated exposure to psychostimulants results in a progressive and long-lasting facilitation of the locomotor response that is thought to have implications for addiction. Psychostimulants and other drugs of abuse activate in specific brain areas extracellular signal-regulated kinase (ERK), an essential component of a signaling pathway involved in synaptic plasticity and long-term effects of drugs of abuse. Here we have investigated the role of ERK activation in the behavioral sensitization induced by repeated administration of psychostimulants in mice, using SL327, a brain-penetrating selective inhibitor of MAP-kinase/ERK kinase (MEK), the enzyme that selectively activates ERK.

Regulation of cocaine-induced activator protein 1 transcription factors by the extracellular signal-regulated kinase pathway.

Extracellular signal-regulated kinases and activator protein 1 transcription factor have been functionally linked to addiction. It has also been shown that extracellular signal-regulated kinase activation can regulate cocaine-induced expression of c-Fos and FosB, two possible components of activator protein 1. A direct link between extracellular signal-regulated kinases and activator protein 1 activation has, however, remained unexplored.

N-Arylalkylpiperidine urea derivatives as CC chemokine receptor-3 (CCR3) antagonists.

The synthesis and structure-activity relationships of N-arylalkylpiperidylmethyl ureas as antagonists of the CC chemokine receptor-3 (CCR3) are presented. These compounds displayed potent binding to the receptor as well as functional antagonism of eotaxin-elicited effects on eosinophils.

Synthesis and structure-activity relationship of a novel sulfone series of TNF-alpha converting enzyme inhibitors.

Replacement of the amide functionality in IM491 (N-hydroxy-(5S,6S)-1-methyl-6-[[4-(2-methyl-4-quinolinylmethoxy)anilinyl]carbonyl]5-piperidinecarboxamide) with a sulfonyl group led to a new series of alpha,beta-cyclic and beta,beta-cyclic gamma-sulfonyl hydroxamic acids, which were potent TNF-alpha converting enzyme (TACE) inhibitors. Among them, inhibitor 4b (N-hydroxy-(4S,5S)-1-methyl-5-[[4-(2-methyl-4-quinolinylmethoxy)phenyl]sulfonylmethyl]-4-pyrrolidinecarboxamide) exhibited IC50 values of < 1 nM and 180 nM in porcine TACE (pTACE) and cell assays, respectively, with excellent selectivity over MMP-1, -2, -9 and -13 and was orally bioavailable with an F value of 46% in mice.

Sultam hydroxamates as novel matrix metalloproteinase inhibitors.

In this communication we describe the design, synthesis, and evaluation of novel sultam hydroxamates 4 as MMP-2, -9, and -13 inhibitors. Compound 26 was found to be an active inhibitor (MMP-2 IC(50) = 1 nM) with 1000-fold selectivity over MMP-1 and good oral bioavailability (F = 43%) in mouse. An X-ray crystal structure of 26 in MMP-13 confirms the key hydrogen bonds and prime side binding in the active site.

Beyond U0126. Dianion chemistry leading to the rapid synthesis of a series of potent MEK inhibitors.

Employing phenylmalonitrile dianion chemistry, a large number of analogues of MEK inhibitor lead SH053 (IC(50)=140 nM) were rapidly synthesized leading to single digit nM inhibitors, displaying submicromolar AP-1 transcription inhibition in COS-7 cells. Compound 41, exhibiting a MEK IC(50)=12 nM showed ip activity in a TPA-induced ear edema model with an ED(50)=5 mg/kg.

Rational design, synthesis and structure-activity relationships of a cyclic succinate series of TNF-alpha converting enzyme inhibitors. Part 1: lead identification.

Rational design based on the broad spectrum MMP inhibitor CGS 27023A led to the identification of a novel series of cyclic succinate TACE inhibitors. As a mixture of two enantiomers, the lead compound 17b exhibited potent enzyme activity (IC(50)=8 nM) in the inhibition of porcine TNF-alpha converting enzyme (pTACE) and excellent selectivity over aggrecanase and MMP-1, -2 and -9.

Rational design, synthesis and structure-activity relationships of a cyclic succinate series of TNF-alpha converting enzyme inhibitors. Part 2: lead optimization.

Modifications of the lead TACE inhibitor 1 (N-hydroxy-trans-2-[[4-(4-quinolinyloxymethyl)anilinyl]carbonyl]-1-cyclohexanecarboxamide) at the cyclohexyl ring and the quinoline moiety led to the identification of a series of piperidine containing TACE inhibitors with potent activity in the inhibition of TNF-alpha release in the whole blood assay (WBA). The most potent analogue IM491 [N-hydroxy-(5S,6S)-1-methyl-6-[[4-(2-methyl-4-quinolinylmethoxy)anilinyl]carbonyl]-5-piperidinecarboxamide] exhibited an IC(50) value of 20 nM in WBA with excellent selectivity over MMP-1, -2 and -9 and is orally bioavailable with an F value of 43% in beagle dogs.

Receptor density dictates the behavior of a subset of steroid ligands in glucocorticoid receptor-mediated transrepression.

By co-expressing glucocorticoid receptor (GR) and transcriptional reporter systems in GR-deficient Cos-7 cells, we profiled potency and efficacy of a panel of GR ligands as a function of GR expression levels (density). Our results show that potency and efficacy for GR full agonists, such as dexamethasone, in these transrepression assays are affected by receptor density. Intriguingly, receptor density dramatically influenced the behavior of the GR antagonist RU486 or the GR agonist medroxyprogesterone acetate (MPA).

Aggrecan protects cartilage collagen from proteolytic cleavage.

The matrix components responsible for cartilage mechanical properties, type II collagen and aggrecan, are degraded in osteoarthritis through proteolytic cleavage by matrix metalloproteinases (MMPs) and aggrecanases, respectively. We now show that aggrecan may serve to protect cartilage collagen from degradation. Although collagen in freeze-thawed cartilage depleted of aggrecan was completely degraded following incubation with MMP-1, collagen in cartilage with intact aggrecan was not.

Discovery of N-hydroxy-2-(2-oxo-3-pyrrolidinyl)acetamides as potent and selective inhibitors of tumor necrosis factor-alpha converting enzyme (TACE).

New inhibitors of tumor necrosis factor-alpha converting enzyme (TACE) were discovered using an N-hydroxy-2-(2-oxo-3-pyrrolidinyl)acetamide scaffold. The series was found to be potent in a porcine TACE (pTACE) assay with IC(50)s typically below 5 nM. For most compounds, selectivity for pTACE relative to MMP-1,-2, and -9 is at least 300-fold.