Optimization of Channel Modulators

Creative Bioarray is committed to providing clients with professional and efficient ion channel modulator optimization services. We generate reliable and critical data in a precise and rapid manner to rapidly evaluate and advance ion channel modulators, and the series, to reach ideal candidate profiles.

Lead Optimization

Lead compounds may often have some defects, such as insufficient activity, unstable chemical structure, high toxicity, poor selectivity, unreasonable pharmacokinetic properties, and so on. Therefore, it is necessary to chemically modify the lead compounds and further optimize them to develop them into ideal drugs. This process is called lead optimization and the process is a critical step in drug discovery. Optimization is usually achieved by:

• Discovery of pharmacophores determining pharmacological effects through chemical operation and biological evaluation, providing the opportunity for the development of drugs with high specificity and low toxicity.
• Changing the chemical structure of lead compounds. For example, lead compounds are optimized using bioisosteres.

At present, some progress has been made in the optimization of ion channel modulators. By replacing the cyclohexane ring with more hydrophobic disubstituted phenyl groups, El-Sayed et al. improved the potency of the compounds on potentiating the K_Ca2.2a channel while retaining their subtype selectivity. Bagal et al. achieved a series of selective Na_v1.8 modulators through optimization of biaryl lead and these compounds were shown to be effective in preclinical studies of neuropathic and inflammatory pain.

Fig. 1 Optimization of the selective Na_v1.8 modulator series that have proven efficacy in preclinical pain models. (Bagal, 2015)

Our Services

The research team at Creative Bioarray has accumulated extensive experience in successful drug discovery. Our comprehensive team helps clients evaluate ion channel modulators entering the lead optimization phase and develop unique strategies to expedite the optimization of these compounds and minimize the number of assays required. The process benefits from the support of our dedicated facilities and technologies, including high-throughput screening, molecular modeling, structural characterization, and target/ligand interaction studies. Through a thorough understanding of the structure-activity relationship (SAR), we provide our clients with valuable information on PK, PK/PD correlations. Our services include but limited to:

• Structural optimization of ion channel modulators, for example:
  • Optimization of the linker between pyrimidine and phenyl
  • Optimization of the pyrimidine moiety
  • Optimization of the pyrazole moiety
• PK and PK/PD analysis in rodents or lagomorphs.
• In vitro and in vivo evaluation of metabolism, off-target activities.
• Structural biology evaluations, including structural characterization, target/ligand interaction, and so on.
• Scale-up synthesis for small-molecule compounds.

Successful drug discovery requires a relentless focus on quality throughout the process. Our ion channel modulator optimization services aim to help customers achieve the following goals:

• Improve potency against ion channels
• Improve drug selectivity and drug stability
• Extend drug action time and reduce toxic side effects
• Improve passive permeability and solubility
• Improve drug absorption and increase the bioavailability
• Minimize transporter interactions and metabolism

The drug development team at Creative Bioarray is composed of experts in the fields of pharmacy, biology, and chemistry, and is committed to providing clients with comprehensive scientific services in ion channel drug discovery. Our expert lead optimization services will maximize your odds of delivering drug candidates. If you are interested in our scientific services, please contact us for more details.

Reference

1. Bagal, S. K.; et al. Discovery and optimization of selective Nav1. 8 modulator series that demonstrate efficacy in preclinical models of pain. ACS medicinal chemistry letters, 2015, 6(6): 650-654.