3 research outputs found
Property-Based Optimization of Hydroxamate-Based γ‑Lactam HDAC Inhibitors to Improve Their Metabolic Stability and Pharmacokinetic Profiles
Hydroxamate-based HDAC inhibitors have promising anticancer
activities
but metabolic instability and poor pharmacokinetics leading to poor
in vivo results. QSAR and PK studies of HDAC inhibitors showed that
a γ-lactam core and a modified cap group, including halo, alkyl,
and alkoxy groups with various carbon chain linkers, improved HDAC
inhibition and metabolic stability. The biological properties of the
γ-lactam HDAC inhibitors were evaluated; the compound designated <b>8f</b> had potent anticancer activity and high oral bioavailability
Property-Based Optimization of Hydroxamate-Based γ‑Lactam HDAC Inhibitors to Improve Their Metabolic Stability and Pharmacokinetic Profiles
Hydroxamate-based HDAC inhibitors have promising anticancer
activities
but metabolic instability and poor pharmacokinetics leading to poor
in vivo results. QSAR and PK studies of HDAC inhibitors showed that
a γ-lactam core and a modified cap group, including halo, alkyl,
and alkoxy groups with various carbon chain linkers, improved HDAC
inhibition and metabolic stability. The biological properties of the
γ-lactam HDAC inhibitors were evaluated; the compound designated <b>8f</b> had potent anticancer activity and high oral bioavailability
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