molecules of the month

The Genentech transient receptor potential ankyrin 1 (TRPA1) inhibitor (“compound 20”) is an ion channel inhibitor with a binding site and mechanism of action characterized by cryo-EM. Structural information for ion-channel targets is rare as X-ray co-crystal structures of membrane-bound proteins are difficult to obtain. The article is an interesting case study for using conformational analysis to improve drug molecules, and the authors highlight several interesting attempted linker rigidification strategies. Compound 20 is orally efficacious in a guinea pig asthma model demonstrating a substantial reduction in inflammatory response due to BALF infiltrates in the airways around 10 mg/kg BID.