- Fragment-based lead discovery of a novel class of small molecule antagonists of neuropeptide B/W receptor subtype 1 (GPR7)
-
Here, we report the discovery of a new class of NPBWR1 antagonists identified from a fragment-based screen. Compound 1 (cAMP IC50 = 250 μM; LE = 0.29) emerged as an initial hit. Further optimization of 1 by SAR-by-catalogue and chemical modification produced 21a (cAMP IC50 = 30 nM; LE = 0.39) with a 6700-fold increase in potency from fragment 1. Somewhat surprisingly, Schild analysis of compound 21a suggested that in vitro inhibition of NPW-mediated effects on upon cAMP accumulation were saturable, and that compound 21a dose-dependently increased [125I]-hNPW23 dissociation rate constants from NPBWR1 in kinetic binding studies. Collectively, these data are inconsistent with a classic surmountable, orthosteric mechanism of inhibition. The benzimidazole inhibitors reported herein may therefore represent a mechanistically differentiated class of compounds with which to form a better appreciation of the pharmacology and physiological roles of this central neuropeptide system.
- Moningka, Remond,Romero, F. Anthony,Hastings, Nicholas B.,Guo, Zhiqiang,Wang, Ming,Di Salvo, Jerry,Li, Ying,Trusca, Dorina,Deng, Qiaoling,Tong, Vincent,Terebetski, Jenna L.,Ball, Richard G.,Ujjainwalla, Feroze
-
-
- TRIAZOLE COMPOUNDS AS ANTIVIRALS
-
The present invention discloses compounds of Formula I: wherein the variables in Formula I are defined as described herein. Also disclosed are pharmaceutical compositions containing such compounds and methods for using the compounds of Formula I in the prevention or treatment of HCV infection.
- -
-
Paragraph 0256
(2014/01/18)
-
- NOVEL COMPOUNDS AS ANTAGONISTS OR INVERSE AGONISTS FOR OPIOID RECEPTORS
-
This invention relates to novel compounds which are antagonists or inverse agonists at one or more of the opioid receptors, to pharmaceutical compositions containing them, to processes for their preparation, and to their use in therapy.
- -
-
Page/Page column 94
(2010/09/07)
-
- INHIBITORS OF 11-BETA-HYDROXYSTEROID DEHYDROGENASE 1
-
The present invention discloses novel compounds of Formula (I): having 11β-HSD type 1 antagonist activity, as well as methods for preparing such compounds. In another embodiment, the invention discloses pharmaceutical compositions comprising compounds of Formula I, as well as methods of using the compounds and compositions to treat diabetes, hyperglycemia, obesity, hypertension, hyperlipidemia, metabolic syndrome, and other conditions associated with 11β-HSD type 1 activity.
- -
-
Page/Page column 37
(2008/06/13)
-
- INHIBITORS OF 11-BETA-HYDROXYSTEROID DEHYDROGENASE 1
-
The present invention discloses novel compounds of Formula I: having 11 Beta-HSD type 1 antagonist activity, as well as methods for preparing such compounds. In another embodiment, the invention discloses pharmaceutical compositions comprising compounds of Formula I, as well as methods of using the compounds and compositions to treat diabetes, hyperglycemia, obesity, hypertension, hyperlipidemia, metabolic syndrome, and other conditions associated with 11Beta-HSD type 1 activity. X-17377
- -
-
Page/Page column 40
(2008/06/13)
-
- 5-HT2A receptor inverse agonists
-
Disclosed herein is a new class of pyrazole compounds which act at the 5HT2A receptors.
- -
-
-
- Small molecule modulators of non-endogenous, constitutively activated human serotonin receptors
-
Disclosed herein are non-endogenous, constitutively activated forms of the human 5-HT2A and human 5-HT2C receptors and uses of such receptors to screen candidate compounds. Further disclosed herein are candidate compounds identified by the screening method which act at the 5HT2A receptors. Yet further disclosed is a new class of compounds which act at the 5HT2A receptors.
- -
-
-
- Transition metal catalysed cross-coupling between benzylic halides and aryl nucleophiles. Synthesis of some toxicologically interesting tetrachlorobenzyltoluenes
-
The aryl-benzyl cross-coupling in the presence of copper-, nickel- and palladium-catalysts has been investigated with a number of chlorine- and methyl-substituted arylmetal compounds ArM (M = MgBr, ZnCl) and (substituted) benzylic halides ArCH2X. The results have been applied in the selective synthesis of some toxicologically interesting tetrachlorobenzyltoluenes.
- De Lang, Robbert-Jan,Van Hooijdonk, Marcel J.C.M.,Brandsma, Lambert,Kramer, Hester,Seinen, Willem
-
p. 2953 - 2966
(2007/10/03)
-
- Synthesis of regiospecifically meso-functionalized tetraarylporphyrins via arylbis(2-pyrrolyl)methanes
-
This paper describes the synthesis of three new porphyrins 1-3 of alternate A2B2 structure, by condensation of arylbis(2-pyrrolyl)methanes and arylaldehydes bearing suitable reactive substituents for further synthetic manipulations. This synthetic approach allows to place the reactive groups selectively on the 5,15 meso-aryls. The new porphyrins feature an ortho-nitro group in the case of 1 and a protected paraethynyl group in compounds 2 and 3. Porphyrin l, after reduction of the nitro group, is a useful intermediate for the preparation of cage or regiospecifically bis-tailed porphyrins. Compounds 2 and 3, after deprotection and Glaser-Hay coupling should give linear polymers (molecular wires) suitable for electron-transfer and light-harvesting processes.
- Banfi, Stefano,Manfredi, Amedea,Pozz, Gianluca,Quici, Silvio,Trebicka, Artan
-
p. 179 - 185
(2007/10/03)
-