1037206-46-4Relevant articles and documents
Discovery of Chromane Containing Hepatitis C Virus (HCV) NS5A Inhibitors with Improved Potency against Resistance-Associated Variants
Yu, Wensheng,Tong, Ling,Hu, Bin,Zhong, Bin,Hao, Jinglai,Ji, Tao,Zan, Shuai,Coburn, Craig A.,Selyutin, Oleg,Chen, Lei,Rokosz, Laura,Agrawal, Sony,Liu, Rong,Curry, Stephanie,McMonagle, Patricia,Ingravallo, Paul,Asante-Appiah, Ernest,Chen, Shiying,Kozlowski, Joseph A.
, p. 10228 - 10243 (2016)
The discovery of potent and pan-genotypic HCV NS5A inhibitors faces many challenges including the significant diversity among genotypes, substantial potency shift conferred on some key resistance-associated variants, inconsistent SARs between different genotypes and mutants, and the lacking of models of inhibitor/protein complexes for rational inhibitor design. As part of ongoing efforts on HCV NS5A inhibition at Merck, we now describe the discovery of a novel series of chromane containing NS5A inhibitors. SAR studies around the "Z" group of the tetracyclic indole scaffold explored fused bicyclic rings as alternates to the phenyl group of elbasvir (1, MK-8742) and identified novel chromane and 2,3-dihydrobenzofuran derivatives as "Z" group replacements offered good potency across all genotypes. This effort, incorporating the C-1 fluoro substitution at the tetracyclic indole core, led to the discovery of a new series of NS5A inhibitors, such as compounds 14 and 25-28, with significantly improved potency against resistance-associated variants, such as GT2b, GT1a Y93H, and GT1a L31V. Compound 14 also showed reasonable PK exposures in preclinical species (rat and dog).
CHROMANE-SUBSTITUED TETRACYCLIC COMPOUNDS AND USES THEREOF FOR TREATMENT OF VIRAL DISEASES
-
, (2018/03/09)
Disclosed are novel chromane-substituted tetracyclic compounds of Formula (I), and pharmaceutically acceptable salts thereof, wherein A, A', R2 R3, R4 and R5 are as defined in the description. Also disclosed are compositions comprising a chromane-substituted tetracyclic compound, and methods of using the chromane-substituted tetracyclic compounds for treating or preventing HCV infection in a patient.
Novel Inhibitors of Staphyloxanthin Virulence Factor in Comparison with Linezolid and Vancomycin versus Methicillin-Resistant, Linezolid-Resistant, and Vancomycin-Intermediate Staphylococcus aureus Infections in Vivo
Ni, Shuaishuai,Wei, Hanwen,Li, Baoli,Chen, Feifei,Liu, Yifu,Chen, Wenhua,Xu, Yixiang,Qiu, Xiaoxia,Li, Xiaokang,Lu, Yanli,Liu, Wenwen,Hu, Linhao,Lin, Dazheng,Wang, Manjiong,Zheng, Xinyu,Mao, Fei,Zhu, Jin,Lan, Lefu,Li, Jian
, p. 8145 - 8159 (2017/10/18)
Our previous work (Wang et al. J. Med. Chem. 2016, 59, 4831-4848) revealed that effective benzocycloalkane-derived staphyloxanthin inhibitors against methicillin-resistant Staphylococcus aureus (S. aureus) infections were accompanied by poor water solubility and high hERG inhibition and dosages (preadministration). In this study, 92 chroman and coumaran derivatives as novel inhibitors have been addressed for overcoming deficiencies above. Derivatives 69 and 105 displayed excellent pigment inhibitory activities and low hERG inhibition, along with improvement of solubility by salt type selection. The broad and significantly potent antibacterial spectra of 69 and 105 were displayed first with normal administration in the livers and hearts in mice against pigmented S. aureus Newman, Mu50 (vancomycin-intermediate S. aureus), and NRS271 (linezolid-resistant S. aureus), compared with linezolid and vancomycin. In summary, both 69 and 105 have the potential to be developed as good antibacterial candidates targeting virulence factors.
MORPHOLINE CARBOXAMIDE PROKINETICIN RECEPTOR ANTAGONISTS
-
Page/Page column 42, (2008/06/13)
The present invention is directed to morpholine carboxamide compounds which are antagonists of prokineticin receptors, in particular antagonists of prokineticin 2 receptors, and which are useful in the treatment or prevention of neurological and psychiatr
