Yifang Huang

Macrocyclic BACE inhibitors: Optimization of a micromolar hit to nanomolar leads.

We have identified macrocyclic inhibitors of the aspartic protease BACE, implicated in the etiology of Alzheimers disease. An X-ray structure of screening hit 1 in the BACE active site revealed a hairpin conformation suggesting that constrained macrocyclic derivatives may also bind there. Several of the analogs we prepared were >100x more potent than 1, such as 7 (5 nM K(i)).

The Preparation and Human Muscarinic Receptor Profiling of Oxybutynin and N-Desethyloxybutynin Enantiomers

Oxybutynin (1) is a non-selective muscarinic receptor antagonist that is used clinically for the treatment of urinary incontinence. The major metabolite of oxybutynin in humans is desethyloxybutynin (2). We have prepared the enantiomers of 1 and 2 and evaluated their ability to displace N-CT(3)-scopolamine chloride ((3)H-NMS) binding on human cloned muscarinic m1-5 receptors. Compounds 1 and 2 potently displaced (3)H-NMS binding at m1, m3 and m4 receptors, but were less potent at the m2 and m5 subtypes. However, metabolite 2 was more potent than the parent compound 1 in the binding assay. In general the R enantiomers were more potent than their respective S enantiomers. Therefore, we suggest that the cholinergic side effects associated with 2 may be due to its greater apparent potency with m1 and m3 receptors, especially of its R-enantiomer, when compared with parent drug 1.