115577-03-2Relevant academic research and scientific papers
Design and synthesis of a novel candidate compound NTI-007 targeting sodium taurocholate cotransporting polypeptide [NTCP]-APOA1-HBx-Beclin1-mediated autophagic pathway in HBV therapy
Zhang, Jin,Fu, Lei-Lei,Tian, Mao,Liu, Hao-Qiu,Li, Jing-Jing,Li, Yan,He, Jun,Huang, Jian,Ouyang, Liang,Gao, Hui-Yuan,Wang, Jin-Hui
, p. 976 - 984 (2015/03/04)
Sodium taurocholate cotransporting polypeptide (NTCP) is a multiple transmembrane transporter predominantly expressed in the liver, functioning as a functional receptor for HBV. Through our continuous efforts to identify NTCP as a novel HBV target, we designed and synthesized a series of new compounds based on the structure of our previous compound NT-5. Molecular docking and MD simulation validated that a new compound named NTI-007 can tightly bind to NTCP, whose efficacy was also measured in vitro virological examination and cytotoxicity studies. Furthermore, autophagy was observed in NTI-007 incubated HepG2.2.15 cells, and results of q-PCR and Western blotting revealed that NTI-007 induced autophagy through NTCP-APOA1-HBx-Beclin1-mediated pathway. Taken together, considering crucial role of NTCP in HBV infection, NTCP-mediated autophagic pathway may provide a promising strategy of HBV therapy and given efficacy of NTI-007 triggering autophagy. Our study suggests pre-clinical potential of this compound as a novel anti-HBV drug candidate.
Antirhino/enteroviral vinylacetylene benzimidazoles: A study of their activity and oral plasma levels in mice
Tebbe, Mark J.,Spitzer, Wayne A.,Victor, Frantz,Miller, Shawn C.,Lee, Chris C.,Sattelberg Sr., Thomas R.,McKinney, Emma,Tang, Joseph C.
, p. 3937 - 3946 (2007/10/03)
In an effort to find an orally bioavailable antiviral for the treatment of rhino/enteroviral infections, a series of vinylacetylene benzimidazoles (11a-o, 12, and 18a) was made. Initial studies of this class of antivirals showed that fluorine substitution on the left-hand phenyl ring in combination with the vinylacetylene moiety gave the requisite mix of physical properties to achieve good in vitro antiviral activity as well as respectable oral bioavailability in rhesus monkeys. To ascertain the generality of this finding and to broaden the scope of the structure-activity relationship (SAR), the present study concentrated on fluoro substitution of this class of molecules. The initial antiviral activity for each analogue was measured using human rhinovirus 14 (HRV-14). This served as an indicator of general antiviral activity for SAR purposes. Subsequently, the spectrum of antirhino/enteroviral activity of the more interesting analogues was evaluated through testing against a panel of seven additional rhino/enteroviruses. Broad-spectrum activity was present and consistent for all analogues tested, and it tracked closely with the antiviral activity observed against HRV-14. A simple screening protocol for oral bioavailability was established whereby compounds were administered orally to mice and plasma levels were measured. This procedure facilitated the evaluation of numerous analogues in a rapid manner. The C(max) was used as a measure of oral bioavailability to allow relative ranking of compounds. In general, fluorine substitution directly on the left-hand aromatic ring does give good oral blood levels. However, fluorine incorporation at other positions in the molecule was not as effective at maintaining either the activity or the oral plasma levels. The constructive combination of activity and oral plasma levels was maximized in three derivatives: 11a,e,g.
