GDC-0310 / Roche, Xenon - LARVOL DELTA

Cryo-EM reveals an unprecedented binding site for Na1.7 inhibitors enabling rational design of potent hybrid inhibitors. (PubMed, Elife) - "To this point understanding of the structure-activity relationships of the acylsulfonamide class of Na1.7 inhibitors, exemplified by the clinical development candidate GDC-0310, has been based solely on a single co-crystal structure of an arylsulfonamide inhibitor bound to voltage-sensing domain 4 (VSD4)...This finding enabled the design of a novel hybrid inhibitor series that bridges the aryl- and acylsulfonamide binding pockets and allows for the generation of molecules with substantially differentiated structures and properties. Overall, our study highlights the power of cryo-EM methods to pursue challenging drug targets using iterative and high-resolution structure-guided inhibitor design This work also underscores an important role of the membrane bilayer in the optimization of selective Na channel modulators targeting VSD4."

Journal • Musculoskeletal Pain • Pain

Discovery of Acyl-sulfonamide Na1.7 Inhibitors GDC-0276 and GDC-0310. (PubMed, J Med Chem) - "To further derisk the predicted human pharmacokinetics and enable QD dosing, additional optimization of the scaffold was conducted, resulting in the discovery of a novel series of N-benzyl piperidine Na1.7 inhibitors. Improvement of the metabolic stability by blocking the labile benzylic position led to the discovery of GDC-0310 (2), which possesses improved Na selectivity and pharmacokinetic profile over 1."

Journal • Pain