jm500563g_si_002.cif (28.82 kB)
Second-Generation Antibacterial Benzimidazole Ureas: Discovery of a Preclinical Candidate with Reduced Metabolic Liability
dataset
posted on 2014-11-13, 00:00 authored by Anne-Laure Grillot, Arnaud Le Tiran, Dean Shannon, Elaine Krueger, Yusheng Liao, Hardwin O’Dowd, Qing Tang, Steve Ronkin, Tiansheng Wang, Nathan Waal, Pan Li, David Lauffer, Emmanuelle Sizensky, Jerry Tanoury, Emanuele Perola, Trudy H. Grossman, Tim Doyle, Brian Hanzelka, Steven Jones, Vaishali Dixit, Nigel Ewing, Shengkai Liao, Brian Boucher, Marc Jacobs, Youssef Bennani, Paul S. CharifsonCompound 3 is a potent aminobenzimidazole urea with broad-spectrum
Gram-positive antibacterial activity resulting from dual inhibition
of bacterial gyrase (GyrB) and topoisomerase IV (ParE), and it demonstrates
efficacy in rodent models of bacterial infection. Preclinical in vitro
and in vivo studies showed that compound 3 covalently
labels liver proteins, presumably via formation of a reactive metabolite,
and hence presented a potential safety liability. The urea moiety
in compound 3 was identified as being potentially responsible
for reactive metabolite formation, but its replacement resulted in
loss of antibacterial activity and/or oral exposure due to poor physicochemical
parameters. To identify second-generation aminobenzimidazole ureas
devoid of reactive metabolite formation potential, we implemented
a metabolic shift strategy, which focused on shifting metabolism away
from the urea moiety by introducing metabolic soft spots elsewhere
in the molecule. Aminobenzimidazole urea 34, identified
through this strategy, exhibits similar antibacterial activity as
that of 3 and did not label liver proteins in vivo, indicating
reduced/no potential for reactive metabolite formation.