Structure-activity relationship studies of orally active antimalarial 3,5-substituted 2-aminopyridines.
作者： Diego González Cabrera , Frederic Douelle , Yassir Younis , Tzu-Shean Feng , Claire Le Manach
DOI: 10.1021/JM301476B
关键词:
摘要: In an effort to address potential cardiotoxicity liabilities identified with earlier frontrunner compounds, a number of new 3,5-diaryl-2-aminopyridine derivatives were synthesized. Several compounds exhibited potent antiplasmodial activity against both the multidrug resistant (K1) and sensitive (NF54) strains in low nanomolar range. Some displayed significant reduction potency hERG channel inhibition assay compared previously reported analogues. these analogues demonstrated promising vivo efficacy Plasmodium berghei mouse model will be further evaluated as clinical candidates. The SAR for vitro was delineated.
acs.org
core.ac.uk
sci-hub.se 参考文章(14)
Norio. Miyaura, Akira. Suzuki, Palladium-catalyzed cross-coupling reactions of organoboron compounds Chemical Reviews. ,vol. 95, pp. 2457- 2483 ,(1995) , 10.1021/CR00039A007
Christophe Biot, Kelly Chibale, Novel approaches to antimalarial drug discovery. Infectious disorders drug targets. ,vol. 6, pp. 173- 204 ,(2006) , 10.2174/187152606784112155
Diego González Cabrera, Frederic Douelle, Tzu-Shean Feng, Aloysius T. Nchinda, Yassir Younis, Karen L. White, Quoc Wu, Eileen Ryan, Jeremy N. Burrows, David Waterson, Michael J. Witty, Sergio Wittlin, Susan A. Charman, Kelly Chibale, Novel orally active antimalarial thiazoles Journal of Medicinal Chemistry. ,vol. 54, pp. 7713- 7719 ,(2011) , 10.1021/JM201108K
Craig Jamieson, Elizabeth M. Moir, Zoran Rankovic, Grant Wishart, Medicinal Chemistry of hERG Optimizations: Highlights and Hang-Ups Journal of Medicinal Chemistry. ,vol. 49, pp. 5029- 5046 ,(2006) , 10.1021/JM060379L
S. A. Charman, S. Arbe-Barnes, I. C. Bathurst, R. Brun, M. Campbell, W. N. Charman, F. C. K. Chiu, J. Chollet, J. C. Craft, D. J. Creek, Y. Dong, H. Matile, M. Maurer, J. Morizzi, T. Nguyen, P. Papastogiannidis, C. Scheurer, D. M. Shackleford, K. Sriraghavan, L. Stingelin, Y. Tang, H. Urwyler, X. Wang, K. L. White, S. Wittlin, L. Zhou, J. L. Vennerstrom, Synthetic ozonide drug candidate OZ439 offers new hope for a single-dose cure of uncomplicated malaria Proceedings of the National Academy of Sciences of the United States of America. ,vol. 108, pp. 4400- 4405 ,(2011) , 10.1073/PNAS.1015762108
HM Louis, M Dror IBKevin, KD Ogobara, None, The pathogenic basis of malaria Nature. ,vol. 415, pp. 673- 679 ,(2002) , 10.1038/415673A
Yassir Younis, Frederic Douelle, Tzu-Shean Feng, Diego González Cabrera, Claire Le Manach, Aloysius T. Nchinda, Sandra Duffy, Karen L. White, David M. Shackleford, Julia Morizzi, Janne Mannila, Kasiram Katneni, Ravi Bhamidipati, K. Mohammed Zabiulla, Jayan T. Joseph, Sridevi Bashyam, David Waterson, Michael J. Witty, David Hardick, Sergio Wittlin, Vicky Avery, Susan A. Charman, Kelly Chibale, 3,5-Diaryl-2-aminopyridines as a Novel Class of Orally Active Antimalarials Demonstrating Single Dose Cure in Mice and Clinical Candidate Potential Journal of Medicinal Chemistry. ,vol. 55, pp. 3479- 3487 ,(2012) , 10.1021/JM3001373
Jeremy N. Burrows, Kelly Chibale, Timothy N.C. Wells, The state of the art in anti-malarial drug discovery and development. Current Topics in Medicinal Chemistry. ,vol. 11, pp. 1226- 1254 ,(2011) , 10.2174/156802611795429194
Natarajan Srinivasan, Alexander Yurek-George, A. Ganesan, Rapid deprotection of N-Boc amines by TFA combined with freebase generation using basic ion-exchange resins. Molecular Diversity. ,vol. 9, pp. 291- 293 ,(2005) , 10.1007/S11030-005-4386-8
WS Redfern, L Carlsson, AS Davis, WG Lynch, IL MacKenzie, S Palethorpe, PKS Siegl, I Strang, AT Sullivan, R Wallis, AJ Camm, TG Hammond, Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs : Evidence for a provisional safety margin in drug development Cardiovascular Research. ,vol. 58, pp. 32- 45 ,(2003) , 10.1016/S0008-6363(02)00846-5