posted on 2014-07-10, 00:00authored byPravin S. Shirude, Radha K. Shandil, M. R. Manjunatha, Claire Sadler, Manoranjan Panda, Vijender Panduga, Jitendar Reddy, Ramanatha Saralaya, Robert Nanduri, Anisha Ambady, Sudha Ravishankar, Vasan
K. Sambandamurthy, Vaishali Humnabadkar, Lalit K. Jena, Rudrapatna S. Suresh, Abhishek Srivastava, K. R. Prabhakar, James Whiteaker, Robert E. McLaughlin, Sreevalli Sharma, Christopher B. Cooper, Khisi Mdluli, Scott Butler, Pravin
S. Iyer, Shridhar Narayanan, Monalisa Chatterji
In a previous
report, we described the discovery of 1,4-azaindoles, a chemical series
with excellent in vitro and in vivo antimycobacterial potency through
noncovalent inhibition of decaprenylphosphoryl-β-d-ribose-2′-epimerase
(DprE1). Nevertheless, high mouse metabolic turnover and phosphodiesterase
6 (PDE6) off-target activity limited its advancement. Herein, we report
lead optimization of this series, culminating in potent, metabolically
stable compounds that have a robust pharmacokinetic profile without
any PDE6 liability. Furthermore, we demonstrate efficacy for 1,4-azaindoles
in a rat chronic TB infection model. We believe that compounds from
the 1,4-azaindole series are suitable for in vivo combination and
safety studies.