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Your search keyword '"O. Pineau"' showing total 2 results
Start Over Author "O. Pineau" Publisher american chemical society
2 results on '"O. Pineau"'

1. Discovery of epigenetic regulator I-BET762: lead optimization to afford a clinical candidate inhibitor of the BET bromodomains.

Author

Mirguet O, Gosmini R, Toum J, Clément CA, Barnathan M, Brusq JM, Mordaunt JE, Grimes RM, Crowe M, Pineau O, Ajakane M, Daugan A, Jeffrey P, Cutler L, Haynes AC, Smithers NN, Chung CW, Bamborough P, Uings IJ, Lewis A, Witherington J, Parr N, Prinjha RK, and Nicodème E

Subjects
Animals, Anti-Inflammatory Agents chemical synthesis, Anti-Inflammatory Agents pharmacokinetics, Anti-Inflammatory Agents pharmacology, Antineoplastic Agents chemical synthesis, Antineoplastic Agents pharmacokinetics, Apolipoprotein A-I biosynthesis, Benzodiazepines chemical synthesis, Benzodiazepines pharmacokinetics, Cell Cycle Proteins, Dogs, Epigenesis, Genetic, Humans, Macaca fascicularis, Mice, Models, Molecular, Permeability, Protein Structure, Tertiary, Rats, Stereoisomerism, Structure-Activity Relationship, Antineoplastic Agents pharmacology, Benzodiazepines pharmacology, Nuclear Proteins antagonists & inhibitors, Transcription Factors antagonists & inhibitors
Abstract

The bromo and extra C-terminal domain (BET) family of bromodomains are involved in binding epigenetic marks on histone proteins, more specifically acetylated lysine residues. This paper describes the discovery and structure-activity relationships (SAR) of potent benzodiazepine inhibitors that disrupt the function of the BET family of bromodomains (BRD2, BRD3, and BRD4). This work has yielded a potent, selective compound I-BET762 that is now under evaluation in a phase I/II clinical trial for nuclear protein in testis (NUT) midline carcinoma and other cancers.

Published
2013
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2. Substituted 2-[(4-aminomethyl)phenoxy]-2-methylpropionic acid PPARalpha agonists. 1. Discovery of a novel series of potent HDLc raising agents.

Author

Sierra ML, Beneton V, Boullay AB, Boyer T, Brewster AG, Donche F, Forest MC, Fouchet MH, Gellibert FJ, Grillot DA, Lambert MH, Laroze A, Le Grumelec C, Linget JM, Montana VG, Nguyen VL, Nicodème E, Patel V, Penfornis A, Pineau O, Pohin D, Potvain F, Poulain G, Ruault CB, Saunders M, Toum J, Xu HE, Xu RX, and Pianetti PM

Subjects
Animals, Apolipoprotein A-I genetics, Cholesterol, VLDL blood, Crystallography, X-Ray, Dogs, Dyslipidemias blood, Dyslipidemias drug therapy, Humans, Ligands, Mice, Mice, Inbred C57BL, Mice, Transgenic, Models, Molecular, PPAR alpha chemistry, Propionates pharmacokinetics, Propionates pharmacology, Protein Structure, Tertiary, Rats, Rats, Wistar, Structure-Activity Relationship, Thiazoles pharmacokinetics, Thiazoles pharmacology, Triglycerides blood, Cholesterol, HDL blood, PPAR alpha agonists, Propionates chemical synthesis, Thiazoles chemical synthesis
Abstract

The peroxisome proliferator activated receptors PPARalpha, PPARgamma, and PPARdelta are ligand-activated transcription factors that play a key role in lipid homeostasis. The fibrates raise circulating levels of high-density lipoprotein cholesterol and lower levels of triglycerides in part through their activity as PPARalpha agonists; however, the low potency and restricted selectivity of the fibrates may limit their efficacy, and it would be desirable to develop more potent and selective PPARalpha agonists. Modification of the selective PPARdelta agonist 1 (GW501516) so as to incorporate the 2-aryl-2-methylpropionic acid group of the fibrates led to a marked shift in potency and selectivity toward PPARalpha agonism. Optimization of the series gave 25a, which shows EC50 = 4 nM on PPARalpha and at least 500-fold selectivity versus PPARdelta and PPARgamma. Compound 25a (GW590735) has been progressed to clinical trials for the treatment of diseases of lipid imbalance.

Published
2007
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