149520-94-5Relevant articles and documents
New geldanamycin derivatives with anti Hsp properties by mutasynthesis
Hermane, Jekaterina,Eichner, Simone,Mancuso, Lena,Schr?der, Benjamin,Sasse, Florenz,Zeilinger, Carsten,Kirschning, Andreas
supporting information, p. 5269 - 5278 (2019/06/07)
Mutasynthetic supplementation of the AHBA blocked mutant strain of S. hygroscopicus, the geldanamycin producer, with 21 aromatic and heteroaromatic amino acids provided new nonquinoid geldanamycin derivatives. Large scale (5 L) fermentation provided four new derivatives in sufficient quantity for full structural characterisation. Among these, the first thiophene derivative of reblastatin showed strong antiproliferative activity towards several human cancer cell lines. Additionally, inhibitory effects on human heat shock protein Hsp90α and bacterial heat shock protein from H. pylori HpHtpG were observed, revealing strong displacement properties for labelled ATP and demonstrating that the ATP-binding site of Hsps is the target site for the new geldanamycin derivatives.
Discovery of 6-(Aminomethyl)-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2- α]pyrimidine-2-carboxamides as potent, selective dipeptidyl peptidase-4 (DPP4) inhibitors
Meng, Wei,Brigance, Robert P.,Chao, Hannguang J.,Fura, Aberra,Harrity, Thomas,Marcinkeviciene, Jovita,O'connor, Stephen P.,Tamura, James K.,Xie, Dianlin,Zhang, Yaqun,Klei, Herbert E.,Kish, Kevin,Weigelt, Carolyn A.,Turdi, Huji,Wang, Aiying,Zahler, Robert,Kirby, Mark S.,Hamann, Lawrence G.
experimental part, p. 5620 - 5628 (2010/10/20)
Continued structure-activity relationship (SAR) exploration within our previously disclosed azolopyrimidine containing dipeptidyl peptidase-4 (DPP4) inhibitors led us to focus on an imidazolopyrimidine series in particular. Further study revealed that by replacing the aryl substitution on the imidazole ring with a more polar carboxylic ester or amide, these compounds displayed not only increased DPP4 binding activity but also significantly reduced human ether-à-go-go related gene (hERG) and sodium channel inhibitory activities. Additional incremental adjustment of polarity led to permeable molecules which exhibited favorable pharmacokinetic (PK) profiles in preclinical animal species. The active site binding mode of these compounds was determined by X-ray crystallography as exemplified by amide 24c. A subsequent lead molecule from this series, (+)-6-(aminomethyl)-5-(2,4-dichlorophenyl)-N-(1-ethyl-1H- pyrazol-5-yl)-7-methylimidazo[1,2-a]pyrimidine-2-carboxamide (24s), emerged as a potent, selective DPP4 inhibitor that displayed excellent PK profiles and in vivo efficacy in ob/ob mice.