335243-50-0Relevant academic research and scientific papers
Stimulation of glucose-dependent insulin secretion by a potent, selective sst3 antagonist
Pasternak, Alexander,Feng, Zhe,De Jesus, Reynalda,Ye, Zhixiong,He, Shuwen,Dobbelaar, Peter,Bradley, Scott A.,Chicchi, Gary G.,Tsao, Kwei-Lan,Trusca, Dorina,Eiermann, George J.,Li, Cai,Feng, Yue,Wu, Margaret,Shao, Qing,Zhang, Bei B.,Nargund, Ravi,Mills, Sander G.,Howard, Andrew D.,Yang, Lihu,Zhou, Yun-Ping
, p. 289 - 293 (2012)
This letter provides the first pharmacological proof of principle that the sst3 receptor mediates glucose-stimulated insulin secretion (GSIS) from pancreatic β-cells. To enable these studies, we identified the selective sst3 antagonist (1R,3R)-3-(5-phenyl-1H-imidazol-2-yl)-1- (tetrahydro-2H-pyran-4-yl)-2,3,4,9-tetrahydro-1H-β-carboline (5a), with improved ion channel selectivity and mouse pharmacokinetic properties as compared to previously described tetrahydro-β-carboline imidazole sst3 antagonists. We demonstrated that compound 5a enhances GSIS in pancreatic β-cells and blocks glucose excursion induced by dextrose challenge in ipGTT and OGTT models in mice. Finally, we provided strong evidence that these effects are mechanism-based in an ipGTT study, showing reduction of glucose excursion in wild-type but not sst3 knockout mice. Thus, we have shown that antagonism of sst3 represents a new mechanism with potential in treating type 2 diabetes mellitus.
METHOD FOR INHIBITING INFLAMMATION and PRO-INFLAMMATORY CYTOKINE/CHEMOKINE EXPRESSION USING A GHRELIN ANALOGUE
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Paragraph 0485, (2016/08/17)
The present invention provides a method of ameliorating inflammation, inhibiting proinflammatory cytokine and/or chemokine expression and treating various diseases and/or conditions incidental to the onset of inflammation, in a subject in need of treatment for such conditions, by administering select analogues of native hGhrelin.
Substrate Fragmentation for the Design of M. tuberculosis CYP121 Inhibitors
Kavanagh, Madeline E.,Gray, Janine L.,Gilbert, Sophie H.,Coyne, Anthony G.,McLean, Kirsty J.,Davis, Holly J.,Munro, Andrew W.,Abell, Chris
, p. 1924 - 1935 (2016/10/06)
The cyclo-dipeptide substrates of the essential M. tuberculosis (Mtb) enzyme CYP121 were deconstructed into their component fragments and screened against the enzyme. A number of hits were identified, one of which exhibited an unexpected inhibitor-like binding mode. The inhibitory pharmacophore was elucidated, and fragment binding affinity was rapidly improved by synthetic elaboration guided by the structures of CYP121 substrates. The resulting inhibitors have low micromolar affinity, good predicted physicochemical properties and selectivity for CYP121 over other Mtb P450s. Spectroscopic characterisation of the inhibitors′ binding mode provides insight into the effect of weak nitrogen-donor ligands on the P450 heme, an improved understanding of factors governing CYP121–ligand recognition and speculation into the biological role of the enzyme for Mtb.
SAR exploration at the C-3 position of tetrahydro-β-carboline sstr3 antagonists
He, Shuwen,Dobbelaar, Peter H.,Guo, Liangqin,Ye, Zhixiong,Liu, Jian,Jian, Tianying,Truong, Quang,Shah, Shrenik K.,Du, Wu,Qi, Hongbo,Bakshi, Raman K.,Hong, Qingmei,Dellureficio, James D.,Sherer, Edward,Pasternak, Alexander,Feng, Zhe,Reibarkh, Mikhail,Lin, Melissa,Samuel, Koppara,Reddy, Vijay B.,Mitelman, Stan,Tong, Sharon X.,Chicchi, Gary G.,Tsao, Kwei-Lan,Trusca, Dorina,Wu, Margaret,Shao, Qing,Trujillo, Maria E.,Fernandez, Guillermo,Nelson, Donald,Bunting, Patricia,Kerr, Janet,Fitzgerald, Patrick,Morissette, Pierre,Volksdorf, Sylvia,Eiermann, George J.,Li, Cai,Zhang, Bei B.,Howard, Andrew D.,Zhou, Yun-Ping,Nargund, Ravi P.,Hagmann, William K.
, p. 1529 - 1535 (2016/07/27)
MK-4256, a tetrahydro-β-carboline sstr3 antagonist, was discontinued due to a cardiovascular (CV) adverse effect observed in dogs. Additional investigations revealed that the CV liability (QTc prolongation) was caused by the hERG off-target activity of MK-4256 and was not due to sstr3 antagonism. In this Letter, we describe our extensive SAR effort at the C3 position of the tetrahydro-β-carboline structure. This effort resulted in identification of 5-fluoro-pyridin-2-yl as the optimal substituent on the imidazole ring to balance sstr3 activity and the hERG off-target liability.
Identification of potent non-peptide somatostatin antagonists with sst3 selectivity
Poitout,Roubert,Contour-Galcéra,Moinet,Lannoy,Pommier,Plas,Bigg,Thurieau
, p. 2990 - 3000 (2007/10/03)
Using a solution-phase parallel synthesis strategy, a series of non-peptide somatostatin analogues were prepared, and their binding affinities to the five human somatostatin receptor subtypes (sst1-5) were determined. Imidazolyl derivatives 2 w
Novel non-peptide ligands for the somatostatin sst3 receptor
Moinet, Christophe,Contour-Galcera, Marie-Odile,Poitout, Lydie,Morgan, Barry,Gordon, Tom,Roubert, Pierre,Thurieau, Christophe
, p. 991 - 995 (2007/10/03)
A series of imidazole derivatives has been prepared using high throughput parallel synthesis. Several compounds showed high affinity (Ki in 10-6-10-8M range) and selectivity at recombinant human somatostatin receptor subtype 3 (hsst3).
