Manjunatha, Ujjini Havaldar, Rao, Srinivasa P.S., Lakshminarayana, Suresh Bangalore, Kondreddi, Ravinder Reddy, Herve, Maxime Marcel, Bifani, Juan Pablo, Luis, Camacho, Jiricek, Jan, Sarath, Kalapala, Tan, Bee Huat, Nanjundappa, Mahesh Bangalore, Seow Hwee, Ng, Sindhu, Ravindran, Seah, Peck Gee, Thayalan, Pamela, Lee, Boon Heng, Barnes, Whitney, Anne, Goh, Arnab, Chatterjee, Kevin, Pethe, Kuhen, Kelli, Walker, John, Babu, Sreehari, Gu, Feng, Lijun, Zhang, Blasco, Francesca, Beer, David John, Weaver, Margaret, Veronique, Dartois, Glynne, Richard, Thomas, Dick, Smith, Paul William, Diagana, Thierry Tidiane, Vivian, Lim NITD and Ida, Ma (2013) Indolcarboxamide, a promising pre-clinical candidate for the treatment of multi drug resistant tuberculosis. Science Translational Medicine.

Abstract

To combat the drug resistance in tuberculosis, new chemotherapeutics active against multi-drug resistant Mycobacterium tuberculosis are urgently needed. We have identified and characterized the indolcarboxamides as a new class of anti-tubercular bactericidal agents. Genetics and lipid profiling studies identified the molecular target of indolcarboxamides as mmpL3, a transporter of TMM, a promiscuous target essential for mycobacterial cell wall biosynthesis. Two lead candidates NITD-304 and NITD-349 showed a significantly potent anti-TB activity against both drug sensitive and multi-drug resistant clinical Mtb isolates. Both compounds displayed favorable pharmacokinetic properties after oral administration in pre-clinical species. NITD-304 and NITD-349 showed no apparent inhibition of major CYP enzymes and are highly efficacious in both acute and chronic TB mouse efficacy models. Furthermore, we have assessed in vitro and in vivo safety profile of both candidates including two weeks exploratory rat toxicology studies. NITD-304 and NITD-349 show the adequate therapeutic index to justify further development for inclusion in the combination therapies for drug sensitive as well as drug resistant TB.

Item Type:	Article
Additional Information:	J. Med Chem manuscript Kondreddi et al describing all the NCE used in this manuscript has already been OAK approved.
Date Deposited:	13 Oct 2015 13:13
Last Modified:	13 Oct 2015 13:13
URI:	https://oak.novartis.com/id/eprint/10825