- SAR of novel benzothiazoles targeting an allosteric pocket of DENV and ZIKV NS2B/NS3 proteases
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In recent years, dengue virus (DENV) and Zika virus (ZIKV), both mosquito-borne members of the Flaviviridae family, have emerged as intercontinental health issues since their vectors have spread from their tropical origins to temperate climate zones due to climate change and increasing globalization. DENV and ZIKV are positive-sense, single-stranded RNA viruses, whose genomes consist of three structural (capsid, membrane precursor, envelope) and seven non-structural (NS) proteins, all of which are initially expressed as a single precursor polyprotein. For virus maturation, the polyprotein processing is accomplished by host proteases and the viral NS2B/NS3 protease complex, whose inhibitors have been shown to be effective antiviral agents with loss of viral pathogenicity. In this work, we elucidate new structure–activity relationships of benzo[d]thiazole-based allosteric NS2B/NS3 inhibitors. We developed a new series of Y–shaped inhibitors, which, with its larger hydrophobic contact surface, should bind to previously unaddressed regions of the allosteric NS2B/NS3 binding pocket. By scaffold-hopping, we varied the benzo[d]thiazole core and identified benzofuran as a new lead scaffold shifting the selectivity of initially ZIKV-targeting inhibitors to higher activities towards the DENV protease. In addition, we were able to increase the ligand efficiency from 0.27 to 0.41 by subsequent inhibitor truncation and identified N-(5,6-dihydroxybenzo[d]thiazol-2-yl)-4-iodobenzamide as a novel sub-micromolar NS2B/NS3 inhibitor. Utilizing cell-based assays, we could prove the antiviral activity in cellulo. Overall, we report new series of sub-micromolar allosteric DENV and ZIKV inhibitors with good efficacy profile in terms of cytotoxicity and protease inhibition selectivity.
- Barthels, Fabian,Gellert, Andrea,Hammerschmidt, Stefan Josef,Kopp, Katja,Maus, Hannah,Millies, Benedikt,Ruggieri, Alessia,Schirmeister, Tanja
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- Design, synthesis and biological evaluation of N1-(isoquinolin-5-yl)-N2-phenylpyrrolidine-1,2-dicarboxamide derivatives as potent TRPV1 antagonists
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Reported herein is the design, synthesis, and pharmacologic evaluation of a class of TRPV1 antagonists constructed on a N1-(isoquinolin-5-yl)-N2-phenylpyrrolidine-1,2-dicarboxamide platform that evolved from a 5-aminoisoquinoline urea lead. Advancing the SAR of this series led to the eventual identification of 3b, comprising a p-Br substituted phenyl. In a TRPV1 functional assay, using cells expressing recombinant human TRPV1 channels, 3b displayed potent antagonism activated by capsaicin (IC50 = 0.084 μM) and protons (IC50 = 0.313 μM). In the preliminary analgesic and body temperature tests, 3b exhibited good efficacy in capsaicin-induced and heat-induced pain models and without hyperthermia side-effect. On the basis of its superior profiles, 3b could be considered as the lead candidate for the further development of antinociceptive drugs.
- Gao, Mingxiang,Nie, Cunbin,Li, Jinyu,Song, Beibei,Cheng, Xinru,Sun, Erying,Yan, Lin,Qian, Hai
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p. 100 - 108
(2018/10/05)
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- Synthesis of Analogues of BCTC Incorporating a Pyrrolidinyl Linker and Biological Evaluation as Transient Receptor Potential Vanilloid 1 Antagonists
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A series of novel pyrrolidinyl linker TRPV1 antagonists were prepared in an effort to lower the hyperthermic side-effects of first-generation antagonist BCTC. These compounds were investigated for antagonism of hTRPV1 activation by capsaicin and acid in vitro. Preliminary results suggested the compounds 10a, 10b, 10c and 10j had favorable TRPV1 antagonism activity. In further studies in vivo, 10b, comparable to BCTC, showed potent analgesic activity in capsaicin-induced and heat-induced pain models. In addition, 10b indicated a reduced risk of body temperature elevation. All of these demonstrated that 10b can be considered as a safe candidate for the further development of analgesic drugs. A series of novel pyrrolidinyl linker TRPV1 antagonists were prepared in an effort to lower the hyperthermic side-effects of first-generation antagonist BCTC. These compounds were investigated for antagonism of hTRPV1 activation by capsaicin and acid in vitro. Preliminary results suggested the compounds 10a, 10b, 10c and 10j had favorable TRPV1 antagonism activity. In further studies in vivo, 10b, comparable to BCTC, showed potent analgesic activity in capsaicin-induced and heat-induced pain models. In addition, 10b indicated a reduced risk of body temperature elevation. All of these demonstrated that 10b can be considered as a safe candidate for the further development of analgesic drugs.
- Yan, Lin,Wang, Jingjie,Pan, Miaobo,Qiu, Qianqian,Huang, Wenlong,Qian, Hai
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p. 306 - 311
(2016/02/10)
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- Proline bis-amides as potent dual orexin receptor antagonists
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A series of OX2R/OX1R dual orexin antagonists was prepared based on a proline bis-amide identified as a screening lead. Through a combination of classical and library synthesis, potency enhancing replacements for both amide portions
- Bergman, Jeffrey M.,Roecker, Anthony J.,Mercer, Swati P.,Bednar, Rodney A.,Reiss, Duane R.,Ransom, Richard W.,Meacham Harrell,Pettibone, Douglas J.,Lemaire, Wei,Murphy, Kathy L.,Li, Chunze,Prueksaritanont, Thomayant,Winrow, Christopher J.,Renger, John J.,Koblan, Kenneth S.,Hartman, George D.,Coleman, Paul J.
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p. 1425 - 1430
(2008/12/21)
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- HYDROXAMIC ACID DERIVATIVES
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Novel hydroxamic acid derivatives, e.g., of formula (I), wherein R1, R2, R3 and R4 are as defined, are found to be useful as pharmaceuticals, e.g., for the suppression of TNF release and the treatment of autoimm
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Page/Page column 27
(2008/06/13)
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