21448-77-1Relevant academic research and scientific papers
Discovery of GS-9669, a thumb site II non-nucleoside inhibitor of NS5B for the treatment of genotype 1 chronic hepatitis C infection
Lazerwith, Scott E.,Lew, Willard,Zhang, Jennifer,Morganelli, Philip,Liu, Qi,Canales, Eda,Clarke, Michael O.,Doerffler, Edward,Byun, Daniel,Mertzman, Michael,Ye, Hong,Chong, Lee,Xu, Lianhong,Appleby, Todd,Chen, Xiaowu,Fenaux, Martijn,Hashash, Ahmad,Leavitt, Stephanie A.,Mabery, Eric,Matles, Mike,Mwangi, Judy W.,Tian, Yang,Lee, Yu-Jen,Zhang, Jingyu,Zhu, Christine,Murray, Bernard P.,Watkins, William J.
supporting information, p. 1893 - 1901 (2014/04/03)
Investigation of thiophene-2-carboxylic acid HCV NS5B site II inhibitors, guided by measurement of cell culture medium binding, revealed the structure-activity relationships for intrinsic cellular potency. The pharmacokinetic profile was enhanced through incorporation of heterocyclic ethers on the N-alkyl substituent. Hydroxyl groups were incorporated to modulate protein binding. Intrinsic potency was further improved through enantiospecific introduction of an olefin in the N-acyl motif, resulting in the discovery of the phase 2 clinical candidate GS-9669. The unexpected activity of this compound against the clinically relevant NS5B M423T mutant, relative to the wild type, was shown to arise from both the N-alkyl substituent and the N-acyl group.
Ring-opening of Some Radicals containing the Cyclopropylmethyl System
Beckwith, Athelstan L. J.,Moad, Graeme
, p. 1473 - 1482 (2007/10/02)
Mono- and bi-cyclic radicals containing the cyclopropylmethyl system are readily generated by interaction of the appropriate halides with triphenyl- or tributyl-stannane.Each radical studied underwent ring-opening by fission of the more substituted βγ-bond.In the case of the secondary radical (12b) the new double bond was formed preferentially in the trans-configuration.Rate constants, which cannot be determined with high accuracy by this method, lie in the range 1E7-3E8 s-1 at 25 deg C.When generated by the flow method in the e.s.r. cavity α-hydroxycyclopropylmethyl radicals undergo β-fission followed by 1,5-hydrogen atom t ransfer to afford enoxyl radicals.The latter reaction occurs more slowly in water than in non-polar solvents.The rigid hydroxynortricyclyl (43) undergoes preferential fission of the less substituted βγ-bond, possibly because of the dipolar nature of the transition state.
