1421703-70-9

Upstream product

• 2339-78-8 1,2-dichloro-4-fluoro-5-nitrobenzene 
• 87120-72-7 1-(tert-butoxycarbonyl)-4-aminopiperidine 

Downstream Products

• 1421703-82-3 tert-butyl 4-((2-amino-4,5-dichlorophenyl)amino)piperidine-1-carboxylate 
• 1421703-64-1 C₂₅H₃₁Cl₂N₅O 

Relevant academic research and scientific papers

Optimization of a novel series of TRPV4 antagonists with in vivo activity in a model of pulmonary edema

High-throughput screening and subsequent hit optimization identified 1-piperidinylbenzimidazoles, exemplified by compound 1, as TRPV4 inhibitors. Lead optimization identified potent TRPV4 blocker 19, which has good target activity and pharmacokinetic properties. Inhibitor 19 was then profiled in an in vivo rat model, demonstrating its ability to inhibit TRPV4-mediated pulmonary edema.

Optimization of a Series of Mu Opioid Receptor (MOR) Agonists with High G Protein Signaling Bias

While mu opioid receptor (MOR) agonists are especially effective as broad-spectrum pain relievers, it has been exceptionally difficult to achieve a clear separation of analgesia from many problematic side effects. Recently, many groups have sought MOR agonists that induce minimal βarrestin-mediated signaling because MOR agonist-treated βarrestin2 knockout mice were found to display enhanced antinociceptive effects with significantly less respiratory depression and tachyphylaxis. Substantial data now exists to support the premise that G protein signaling biased MOR agonists can be effective analgesic agents. We recently showed that, within a chemical series, the degree of bias correlates linearly with the magnitude of the respiratory safety index. Herein we describe the synthesis and optimization of piperidine benzimidazolone MOR agonists that together display a wide range of bias (G/βarr2). We identify structural features affecting potency and maximizing bias and show that many compounds have desirable properties, such as long half-lives and high brain penetration.

SIGNALING-BIASED MU OPIOID RECEPTOR AGONISTS

The invention provides -opioid receptor agonists that are analgesic agents and that promote diminished side effects relative to a comparably effective dose of morphine. The side effects that are absent or attenuated include one or more of the following: constipation, respiratory depression, tolerance, dependence, nausea, confusion, sedation, hypotension, and post-treatment withdrawal symptoms.