XEN907

Discovery of XEN907, a spirooxindole blocker of NaV1.7 for the treatment of pain

Starting from the oxindole 2a identified through a high-throughput screening campaign, a series of Na(V)1.7 blockers were developed. Following the elimination of undesirable structural features, preliminary optimization of the oxindole C-3 and N-1 substituents afforded the simplified analogue 9b, which demonstrated a 10-fold increase in target potency versus the original HTS hit. A scaffold rigidification strategy then led to the discovery of XEN907, a novel spirooxindole Na(V)1.7 blocker. This lead compound, which in turn showed a further 10-fold increase in potency, represents a promising structure for further optimization efforts.

Structural basis for NaV1.7 inhibition by pore blockers

Voltage-gated sodium channel Na_V1.7 plays essential roles in pain and odor perception. Na_V1.7 variants cause pain disorders. Accordingly, Na_V1.7 has elicited extensive attention in developing new analgesics. Here we present cryo-EM structures of human Na_V1.7/β1/β2 complexed with inhibitors XEN907, TC-N1752 and Na_V1.7-IN2, explaining specific binding sites and modulation mechanism for the pore blockers. These inhibitors bind in the central cavity blocking ion permeation, but engage different parts of the cavity wall. XEN907 directly causes α- to π-helix transition of DIV-S6 helix, which tightens the fast inactivation gate. TC-N1752 induces π-helix transition of DII-S6 helix mediated by a conserved asparagine on DIII-S6, which closes the activation gate. Na_V1.7-IN2 serves as a pore blocker without causing conformational change. Electrophysiological results demonstrate that XEN907 and TC-N1752 stabilize Na_V1.7 in inactivated state and delay the recovery from inactivation. Our results provide structural framework for Na_V1.7 modulation by pore blockers, and important implications for developing subtype-selective analgesics.

An unexpected cascade reaction of 3-hydroxyoxindoles with coumarin-3-carboxylates to construct 2,3-dihydrobenzofuran spirooxindoles

An unexpected Michael addition-inspired ring-opening/closure cascade reaction of 3-hydroxyoxindoles with coumarin-3-carboxylates was developed to access new dihydrobenzofuran or dihydrobenzothiophene spirooxindoles in 68-98% yields. This reaction not only provides an expedient and convenient method to assemble dihydrobenzofuran spirooxindoles, but also establishes a new reaction mode of coumarin-3-carboxylates. Moreover, it represents the first example of 3-hydroxyoxindoles serving as a C1 synthon possessing dual nucleophilic and electrophilic character with the hydroxyl group as a leaving group. Importantly, this methodology provides a rapid and robust approach to XEN907 analogues.

Dictating the Reactivity of η3-Oxoallyl Pd-Intermediate toward 5- exo-trig Cyclization: Access to Indano-spirooxindoles

A facile synthesis of indanone-fused spirooxindoles is disclosed by directing the reactivity of η³-oxoallyl Pd-intermediate toward 5- exo-trig mode of cyclization. The Pd-catalyzed reaction of the rationally designed starting material 3-arylidene oxindoles with isatin-derived tosylhydrazone afforded the spirooxindoles having all-carbon quaternary center through carbene migratory insertion followed by Heck-type cyclization sequence. The photophysical studies and DFT calculations were conducted to understand their electronic properties. Moreover, the synthesis of XEN 907 analogue is also featured by employing the present methodology.