2 research outputs found
Lead Optimization of a Novel Series of Imidazo[1,2‑<i>a</i>]pyridine Amides Leading to a Clinical Candidate (Q203) as a Multi- and Extensively-Drug-Resistant Anti-tuberculosis Agent
A critical
unmet clinical need to combat the global tuberculosis
epidemic is the development of potent agents capable of reducing the
time of multi-drug-resistant (MDR) and extensively-drug-resistant
(XDR) tuberculosis therapy. In this paper, we report on the optimization
of imidazoÂ[1,2-<i>a</i>]Âpyridine amide (IPA) lead compound <b>1</b>, which led to the design and synthesis of Q203 (<b>50</b>). We found that the amide linker with IPA core is very important
for activity against Mycobacterium tuberculosis H37Rv. Linearity and lipophilicity of the amine part in the IPA
series play a critical role in improving in vitro and in vivo efficacy
and pharmacokinetic profile. The optimized IPAs <b>49</b> and <b>50</b> showed not only excellent oral bioavailability (80.2% and
90.7%, respectively) with high exposure of the area under curve (AUC)
but also displayed significant colony-forming unit (CFU) reduction
(1.52 and 3.13 log<sub>10</sub> reduction at 10 mg/kg dosing level,
respectively) in mouse lung
Discovery of Phenylaminopyridine Derivatives as Novel HIV-1 Non-nucleoside Reverse Transcriptase Inhibitors
We identified a novel class of aryl-substituted triazine
compounds as potent non-nucleoside reverse transcriptase inhibitors
(NNRTIs) during a high-throughput screening campaign that evaluated
more than 200000 compounds for antihuman immunodeficiency virus (HIV)
activity using a cell-based full replication assay. Herein, we disclose
the optimization of the antiviral activity in a cell-based assay system
leading to the discovery of compound <b>27</b>, which possessed
excellent potency against wild-type HIV-1 (EC<sub>50</sub> = 0.2 nM)
as well as viruses bearing Y181C and K103N resistance mutations in
the reverse transcriptase gene. The X-ray crystal structure of compound <b>27</b> complexed with wild-type reverse transcriptase confirmed
the mode of action of this novel class of NNRTIs. Introduction of
a chloro functional group in the pyrazole moiety dramatically improved
hERG and CYP inhibition profiles, yielding highly promising leads
for further development