2 research outputs found
Design of Substituted Imidazolidinylpiperidinylbenzoic Acids as Chemokine Receptor 5 Antagonists: Potent Inhibitors of R5 HIV‑1 Replication
The
redesign of the previously reported thiophene-3-yl-methyl urea
series, as a result of potential cardiotoxicity, was successfully
accomplished, resulting in the identification of a novel potent series
of CCR5 antagonists containing the imidazolidinylpiperidinyl scaffold.
The main redesign criteria were to reduce the number of rotatable
bonds and to maintain an acceptable lipophilicity to mitigate hERG
inhibition. The structure–activity relationship (SAR) that
was developed was used to identify compounds with the best pharmacological
profile to inhibit HIV-1. As a result, five advanced compounds, <b>6d</b>, <b>6e</b>, <b>6i</b>, <b>6h</b>, and <b>6k</b>, were further evaluated for receptor selectivity, antiviral
activity against CCR5 using (R5) HIV-1 clinical isolates, and in vitro
and in vivo safety. On the basis of these results, <b>6d</b> and <b>6h</b> were selected for further development
Discovery of Aryl Sulfonamides as Isoform-Selective Inhibitors of Na<sub>V</sub>1.7 with Efficacy in Rodent Pain Models
We report on a novel series of aryl
sulfonamides that act as nanomolar
potent, isoform-selective inhibitors of the human sodium channel hNa<sub>V</sub>1.7. The optimization of these inhibitors is described. We
aimed to improve potency against hNa<sub>V</sub>1.7 while minimizing
off-target safety concerns and generated compound <b>3</b>.
This agent displayed significant analgesic effects in rodent models
of acute and inflammatory pain and demonstrated that binding to the
voltage sensor domain 4 site of Na<sub>V</sub>1.7 leads to an analgesic
effect <i>in vivo</i>. Our findings corroborate the importance
of hNa<sub>V</sub>1.7 as a drug target for the treatment of pain