A series of 2-aminobenzimidazole-based MCH1R antagonists was identified by core replacement of the aminoquinoline lead 1. Subsequent modification of the 2- and 5-positions led to improvement in potency and intrinsic clearance. Compound 25 exhibited good plasma and brain exposure, and attenuated MCH induced food intake at 30mg/kg PO in rats.

Continuing medicinal chemistry studies to identify spiropiperidine-derived NPY Y5 receptor antagonists are described. Aryl urea derivatives of a variety of spiropiperidines were tested for their NPY Y5 receptor binding affinities. Of the spiropiperidines so far examined, spiro[3-oxoisobenzofurane-1(3H),4 '-piperidine] was a useful scaffold for producing orally active NPY Y5 receptor antagonists. Oral administration of 5c significantly inhibited the Y5 agonist-induced food intake in rats with a minimum effective dose of 3 mg/kg. In addition, this compound was efficacious in decreasing body weight in diet-induced obese mice. (C) 2009 Elsevier Ltd. All rights reserved.

Optimization of high-throughput screening hit 1a led to the identification of a novel spiro-piperidine class of melanin-concentrating hormone 1 receptor (MCH-1R) antagonists. Compound 3c was identified as a highly potent and selective MCH-1R antagonist, which has an IC(50) value of 0.09 nM at hMCH-1R. The synthesis and structure-activity relationships of the novel spiro-piperidine MCH-1R antagonists are described.

A series of trans-3-oxospiro[(aza)isobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide derivatives were synthesized to identify potent NPY Y5 receptor antagonists. Of the compounds, 21j showed high Y5 binding affinity, metabolic stability and brain and cerebrospinal fluid (CSF) penetration, and low susceptibility to P-glycoprotein transporters. Oral administration of 21j significantly inhibited the Y5 agonist-induced food intake in rats with a minimum effective dose of 1mg/kg. This compound was selected for proof-of-concept studies in human clinical trials.

Design, syntheses, and structure-activity relationships of a novel class of 2-{3-oxospiro[isobenzofuran-1(3H),4'-piperidin]-1'-yl}benzimidazole NPY Y5 receptor antagonists are described. The benzimidazole structures were newly designed based on the urea linkage of our prototype Y5 receptor antagonists (2 and 3). By optimizing substituents on the benzimidazole core part of the lead compound 5a, we were able to develop a potent, orally available, and brain-penetrable Y5 selective antagonist (5k).

Microwave heating has been applied to the oxidation in the new rutile extraction process developed by the authors in which rutile is extracted from a natural ilmenite ore by oxidation and magnetic separation followed by leaching with diluted acid. Since ilmenite FeTiO3 and pseudobrookite Fe2TiO5 strongly absorb 28 GHz microwave, Australian ilmenite ore mainly composed of FeTiO3 was rapidly heated up to about 1 273 K and oxidized in air with keeping almost constant temperature. As a result, two equilibrium phases of rutile TiO2 and pseudobrookite were quickly formed at microwave power of 1.5 kW. The growth rate of the pseudobrookite phase in the microwave irradiation was found to be much faster than that of the rutile phase in the conventional resistance furnace, indicating a drastic enhancement of the growth rate by the microwave irradiation.

L'invention concerne des composes de formule (I), dans laquelle X1, X2, X3 representent independamment les uns des autres N ou CH, w represente la formule (II), ou la formule (III), et Y represente un groupe de formule (IV). L'invention concerne egalement un sel pharmaceutiquement acceptable des composes. Les composes de l'invention presentent une activite d'antagoniste du recepteur H3 de l'histamine ou une activite agoniste inversee et ils sont utilises dans le traitement et/ou la prevention de l'obesite, du diabete, d'un dysfonctionnement des secretions hormonales, des troubles du sommeil, etc.