Reverse-Design toward Optimized Labeled Chemical Probes – Examples from the Endocannabinoid System

Abstract

Labeled chemical probes are of utmost importance to bring drugs from the laboratory through the clinic and ultimately to market. They support and impact all research and discovery phases: target verification and validation; assay development; lead optimization; and biomarker engagement in the context of preclinical studies and human trials. Probes should display high potency and selectivity as well as fulfill specific criteria in connection with absorption, distribution, metabolism, excretion and toxicology (ADMET) profile. Progress in fields such as imaging and proteomics increased the need for specialized probes to support drug discovery. Labeled probes carrying an additional reporter group are valuable tools to meet specific application requirements, but pose significant challenges in design and construction. In the reverse-design approach, small molecules previously optimized in medicinal chemistry programs form the basis for the generation of such high-quality probes. We discuss the reverse design concept for the generation of labeled probes targeting the endocannabinoid system (ECS), a complex lipid signaling network that plays a key role in many human health and disease conditions. The examples highlighted include diverse reporter units for a range of applications. In several cases the reported probes were the product of mutually rewarding and highly cross-fertilizing collaborations among academic and industry research programs, a strategy that can serve as a blueprint for future probe generation efforts.

EFMC: Trends in Medicinal Chemistry and Chemical Biology

“…Molecular probes support and impact all phases of drug discovery programs, starting with target identification and validation, as well as assay development [9] . They open the way to lead generation, and potentially support preclinical studies and human trials with biomarkers and target engagement tools [10] . Figure 1 illustrates the general ideal of fundamental studies and methodologies needed during drug discovery processes (roots) and the actual aims that can be reached from the easiest ones (low‐hanging fruits) to the most difficult but maybe more rewarding opportunities (high‐hanging fruits).…”

Imaging and Genetic Tools for the Investigation of the Endocannabinoid System in the CNS

“…In contrast, DAGL and NAPE-PLD are preferentially imaged with fluorescent probes [96]. The Van Der Stelt group identified a selective NAPE-PLD inhibitor, LEI-401, which reduced the levels of the synthetic enzyme in a dose-dependent manner [97].…”

Highly Selective Drug-Derived Fluorescent Probes for the Cannabinoid Receptor Type 1 (CB1R)

“…The probes were conceptualized based on a reverse design approach employing synthetic drug-like CB1R ligands with a defined pharmacological profile as starting points. 41 This study led to the discovery of novel and highly selective pyrrole-based CB1R fluorescent probes. Further exploration showcased the versatility of these inverse agonist fluorescent probes for pharmacological time-resolved Förster resonance transfer (TR-FRET) studies and CB1R imaging on live cells.…”