Document Report Card

ID: ALA3286390

Journal: J Med Chem

Title: Lead optimization of 1,4-azaindoles as antimycobacterial agents.

Authors: Shirude PS, Shandil RK, Manjunatha MR, Sadler C, Panda M, Panduga V, Reddy J, Saralaya R, Nanduri R, Ambady A, Ravishankar S, Sambandamurthy VK, Humnabadkar V, Jena LK, Suresh RS, Srivastava A, Prabhakar KR, Whiteaker J, McLaughlin RE, Sharma S, Cooper CB, Mdluli K, Butler S, Iyer PS, Narayanan S, Chatterji M.

Abstract: 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.

CiteXplore: 24874895

DOI: 10.1021/jm500571f