Description: Optimization of novel small molecule agents modulating receptor targets for CNS disease.

In this (ongoing) two-year project Selvita supported a multi-partner collaboration (Client-University-Pharma) from assay development and screening,
through hit identification and hit-to-lead stages and into a phase of work toward optimized leads and candidates using resources in chemistry, biology
and ADME.

Challenges to be addressed: Four interesting hit families were identified in screening but despite promising initial activity there were many challenges
to be addressed, from poorly validated chemistry to sub-optimal physicochemical properties, cytochrome P450 liability and limited metabolic stability.
Target selectivity also required optimization.

Actions taken: Synthetic chemistry approaches were developed to enable a sound exploration of the various hit series, developing SAR and providing insight into how ADME and selectivity limitations could be addressed.

SAR was developed using the productive chemical routes and final compounds were evaluated in a tiered panel of ADME assays at Selvita and within
a biological screening cascade established by Selvita.

A midway snapshot of the project:

Over the first 18 months, >1000 compounds were tested in the assay panel (single-point, counter-screen & IC₅₀).

A chemistry team of four chemists delivered numerous compounds (see graph below) using 3-10 step chemistry and in amounts of 10-200 mg.

The progress in this project is also illustrated by the tracking of potency (pIC50) versus Lipophilic Ligand Efficiency (LLE) where in addition to moving to increasingly potent compounds the project team generated increasingly improved LLE scores which was pleasing given the apparent “lipophile-loving”
nature of the protein target.