233755-70-9Relevant articles and documents
Identification, optimization, and pharmacology of acylurea GHS-R1a inverse agonists
McCoull, William,Barton, Peter,Brown, Alastair J. H.,Bowker, Suzanne S.,Cameron, Jennifer,Clarke, David S.,Davies, Robert D. M.,Dossetter, Alexander G.,Ertan, Anne,Fenwick, Mark,Green, Clive,Holmes, Jane L.,Martin, Nathaniel,Masters, David,Moore, Jane E.,Newcombe, Nicholas J.,Newton, Claire,Pointon, Helen,Robb, Graeme R.,Sheldon, Christopher,Stokes, Stephen,Morgan, David
supporting information, p. 6128 - 6140 (2014/08/18)
Ghrelin plays a major physiological role in the control of food intake, and inverse agonists of the ghrelin receptor (GHS-R1a) are widely considered to offer utility as antiobesity agents by lowering the set-point for hunger between meals. We identified an acylurea series of ghrelin modulators from high throughput screening and optimized binding affinity through structure-activity relationship studies. Furthermore, we identified specific substructural changes, which switched partial agonist activity to inverse agonist activity, and optimized physicochemical and DMPK properties to afford the non-CNS penetrant inverse agonist 22 (AZ-GHS-22) and the CNS penetrant inverse agonist 38 (AZ-GHS-38). Free feeding efficacy experiments showed that CNS exposure was necessary to obtain reduced food intake in mice, and it was demonstrated using GHS-R1a null and wild-type mice that this effect operates through a mechanism involving GHS-R1a.
Synthesis and structure-activity relationships of amide derivatives of (4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene)acetic acid as selective arginine vasopressin V2 receptor agonists
Tsukamoto, Issei,Koshio, Hiroyuki,Kuramochi, Takahiro,Saitoh, Chikashi,Yanai-Inamura, Hiroko,Kitada-Nozawa, Chika,Yamamoto, Eisaku,Yatsu, Takeyuki,Shimada, Yoshiaki,Sakamoto, Shuichi,Tsukamoto, Shin-ichi
scheme or table, p. 3130 - 3141 (2009/09/30)
A series of (4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene)acetamide derivatives was synthesized, and their structure-activity relationships were examined in order to identify potent and selective arginine vasopressin V2 receptor agonists. Attempts to substitute other chemical groups in place of the 2-pyridilmethyl moiety of 1a led to the discovery that potent V2 binding affinity could be obtained with a wide range of functional groups. This structural tolerance allowed for the manipulation of other attributes, such as selectivity against V1a receptor affinity or avoidance of the undesirable inhibition of cytochrome P450 (CYP), without losing potent affinity for the V2 receptor. Some representative compounds obtained in this study were also found to decrease urine volume in awake rats.
Identification and synthesis of major metabolites of Vasopressin V2-receptor agonist WAY-151932, and antagonist, Lixivaptan
Molinari, Albert J.,Trybulski, Eugene J.,Bagli, Jehan,Croce, Susan,Considine, John,Qi, Jian,Ali, Kadum,DeMaio, William,Lihotz, Lynne,Cochran, David
, p. 5796 - 5800 (2008/09/21)
Small molecule agonists and antagonists of the V2-vasopressin receptor have been discovered and have undergone clinical trials. In conjunction with these discovery programs, the synthesis and biological testing of various metabolites associated with these clinical targets were actively pursued. We now report the results of our synthetic efforts and the corresponding biological data generated for several of the metabolites of WAY-151932 and CL-347985 (Lixivaptan).
