Phenyloxyphenyl blockers

V102862, 17, a phenoxyphenyl benzaldehyde semicarbazone was originally described in the literature as an anticonvulsant and was found to be a non-selective sodium channel blocker (IC50 = 610 nM, rat brain Nav1.2) with activity in the Chung assay [46]. It has sub-optimal PK properties and has been used as a starting point to develop several series of sodium channel blockers that replace the labile semicarbazone with a variety of heterocyclic bioisosteres. Replacement with a pyridyl carboxamide, as in 18, keeps the heteroatoms in the same orientation as in 17 with an improvement in potency, IC50 = 96 nM, against rNav1.2, and activity in rat DRGs, IC50 = 101 nM TTXs currents and IC50 = 270 nM TTXr currents [47,48]. The other pyridyl regioisomers were > 20-fold less potent.

Based on PK results, 18 and 19 (IC50 = 123 nM) were evaluated in the Chung model. Dose-dependent reversersal of tactile allodynia was observed with 18 at 3 and 10mg/kg p.o. with an ED50 of 10mg/kg. Anti-allodynic activity for 19 was also observed in the Chung model with an MED of 3 mg/kg p.o. and a therapeutic index (TI) relative to CNS side effects, of 10. This compares favorably to an MED of 100 mg/kg p.o. and a TI of 1 for carbamazepine. It is interesting to note that while most of the compounds in this series were non-selective, 20 (IC50 = 180 nM TTXs rDRG) was about 9-fold TTXs/TTXr selective in rDRGs. The role of the carbox-amide was explored further and based on a previously reported compound, 21 was synthesized providing a potent (rNav1.2 IC50 = 75 nM) and state-dependant blocker that did not possess the carboxamide.

Il L II 18

NH2 F

NH2 F

Il L II 18

Other bioisosteres used to mimic the semicarbazone have included pyrazoles exemplified by 22 which demonstrated activity in the Chung model at 10 mg/kg p.o. [49]. The primary carboxamide was not required for potency, but the distal phenyl was. The nitro group could be replaced with 4-F, 2,4-di-F or hydrogen.

Phenoxyphenyl thiazolidine-2,4-dione 23 and oxazolidine-2,4-dione 24 have been described with activity against Nav1.7 [50]. Additionally, the biaryl analogue, 25, was shown to have similar activity.

f nh

o nn

Additional isosteres include 1H-quinazolin-4-one, benzopyrimidin-4-one 26 and 1,3-thiazin-4-ones [51], and phenoxy- and benzyloxy-hydantoins 27 both with binding activity in rNav1.2 [52].

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