22227-63-0Relevant articles and documents
Discovery of a First-in-Class Gut-Restricted RET Kinase Inhibitor as a Clinical Candidate for the Treatment of IBS
Schenck Eidam, Hilary,Russell, John,Raha, Kaushik,Demartino, Michael,Qin, Donghui,Guan, Huiping Amy,Zhang, Zhiliu,Zhen, Gong,Yu, Haiyu,Wu, Chengde,Pan, Yan,Joberty, Gerard,Zinn, Nico,Laquerre, Sylvie,Robinson, Sharon,White, Angela,Giddings, Amanda,Mohammadi, Ehsan,Greenwood-Van Meerveld, Beverly,Oliff, Allen,Kumar, Sanjay,Cheung, Mui
supporting information, p. 623 - 628 (2018/07/25)
Abdominal pain and abnormal bowel habits represent major symptoms for irritable bowel syndrome (IBS) patients that are not adequately managed. Although the etiology of IBS is not completely understood, many of the functions of the gastrointestinal (GI) tract are regulated by the enteric nervous system (ENS). Inflammation or stress-induced expression of growth factors or cytokines may lead to hyperinnervation of visceral afferent neurons in GI tract and contribute to the pathophysiology of IBS. Rearranged during transfection (RET) is a neuronal growth factor receptor tyrosine kinase critical for the development of the ENS as exemplified by Hirschsprung patients who carry RET loss-of-function mutations and lack normal colonic innervation leading to colonic obstruction. Similarly, RET signaling in the adult ENS maintains neuronal function by contributing to synaptic formation, signal transmission, and neuronal plasticity. Inhibition of RET in the ENS represents a novel therapeutic strategy for the normalization of neuronal function and the symptoms of IBS patients. Herein, we describe our screening effort and subsequent structure-activity relationships (SARs) in optimizing potency, selectivity, and mutagenicity of the series, which led to the discovery of a first-in-class, gut-restricted RET kinase inhibitor, 2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)acetamide (15, GSK3179106), as a clinical candidate for the treatment of IBS. GSK3179106 is a potent, selective, and gut-restricted pyridone hinge binder small molecule RET kinase inhibitor with a RET IC50 of 0.3 nM and is efficacious in vivo.
S-substituted 3,5-dinitrophenyl 1,3,4-oxadiazole-2-thiols and tetrazole-5-thiols as highly efficient antitubercular agents
Karabanovich, Galina,Něme?ek, Jan,Valá?ková, Lenka,Carazo, Alejandro,Kone?ná, Klára,Stola?íková, Ji?ina,Hrabálek, Alexandr,Pavli?, Oto,Pávek, Petr,Vávrová, Kate?ina,Roh, Jaroslav,Klime?ová, Věra
, p. 369 - 383 (2016/12/22)
Two new classes of antitubercular agents, namely 5-alkylsulfanyl-1-(3,5-dinitrophenyl)-1H-tetrazoles and 2-alkylsulfanyl-5-(3,5-dinitrophenyl)-1,3,4-oxadiazoles, and their structure-activity relationships are described. These compounds possessed excellent activity against Mycobacterium tuberculosis, including the clinically isolated multidrug (MDR) and extensively drug-resistant (XDR) strains, with no cross resistance with first or second-line anti-TB drugs. The minimum inhibitory concentration (MIC) values of the most promising compounds reached 0.03 μM. Furthermore, these compounds had a highly selective antimycobacterial effect because they were completely inactive against 4 gram positive and 4 gram negative bacteria and eight fungal strains and had low in vitro toxicity for four mammalian cell lines, including hepatic cell lines HepG2 and HuH7. Although the structure-activity relationship study showed that the presence of two nitro groups is highly beneficial for antimycobacterial activity, the analogues with a trifluoromethyl group instead of one of the nitro groups maintained a high antimycobacterial activity, which indicates the possibility for further structural optimization of this class of antitubercular agents.
Syntheses and evaluation of substituted aromatic hydroxamates and hydroxamic acids that target Mycobacterium tuberculosis
Majewski, Mark W.,Cho, Sanghyun,Miller, Patricia A.,Franzblau, Scott G.,Miller, Marvin J.
supporting information, p. 4933 - 4936 (2015/10/28)
Tuberculosis (TB) continues to remain one of the most threatening diseases in the world. With the emergence of multi-drug resistant (MDR) and extensively drug resistant (XDR) strains, the need to develop new therapies is dire. The syntheses of a focused library of hydroxamates and hydroxamic acids is described, as well as anti-TB activity in the microplate alamar blue assay (MABA). A number of compounds exhibited good activity against Mtb, with notable compounds exhibiting MIC values in the range of 20-0.71 μM. This work suggests that both hydroxamates and their free acids may be incorporated into more complex scaffolds and serve as potential leads for the development of anti-TB agents.
