Figure 4. ‘Flat’ SARs.

The prototypical scaffold of BQCA (compound 8), which is an M1 muscarinic acetylcholine receptor PAM (positive allosteric modulator), was shown to possess a notoriously ‘flat’ or ‘shallow’ structure–activity relationship (SAR). An initial chemical-optimization effort afforded hundreds of analogues (including compound 9) in which R1 and R2 were not fluoro substituents that had very low success rate in potentiating M₁-receptor-mediated calcium mobilization in cell lines (fewer than 5% of compounds were active). Application of the ‘fluorine walk’ identified multiple regions in which fluorine atoms were tolerated and improved M₁-receptor potency, such as in compound 10. A subsequent re-optimization campaign with the optimal fluorine atoms in place was highly productive and led to the discovery of potent M₁-receptor PAMs, such as compound 11. The inset summarizes the effects of modifications of different regions of the BCQA scaffold on different components of the PAM response. EC₅₀, effector concentration for half-maximum response; pK_B, dissociation constant.