Miscellaneous blockers

The known [58] potent cardiac sodium channel blocker 32 was found to inhibit Nav1.7 in a VIPR format (IC50 = 4 mM) and was used to develop a new series of blockers [59]. When injected locally, 32 was active in a dose-dependant manner in the phase II response of the formalin model (MED 1.5 mg), but was inactive when dosed i.v. at 3 mg/kg (13% inhibition). In addition to PK liabilities, it also displayed considerable hERG activity (IC50 = 180 nM, displacement of MK-499 binding). Modifying the basicity of the amine by incorporating it into an amide bond, 33, resulted in a reduction of hERG activity (88% inhib at 10 mM) but with a loss in Nav1.7 activity as well, IC50 = 19.4 mM. Activity against Nav1.7 was regained and a further reduction in hERG activity was realized (Nav1.7 IC50 = 1.3 mM; hERG

IC50 = 7.7 mM) with the pyrrolidine amide, 34. Oral bioavailability was low for this compound (9.4%) and the t1/2 was 0.48 h. It exhibited a 68% reduction in the phase II response in formalin assay at 3mg/kg, i.v. Attempts to replace the p-chlorophenylthiazole side chain resulted mostly in inactive compounds except for replacement with ^-chlorophenyl-1,2,4-oxadiazole and bithiophenemethyl as in 8. Substitution of the methoxy group with larger moieties resulted in reduced potency, but replacement with Cl, CH3 and H were tolerated with slight improvements in potency.

A conformationally constrained analogue 35 was prepared to determine its effects on potency and PK properties. Although potency was slightly diminished (IC50 = 3.6 mM, EP IC50 = 0.21 mM, IC50 = 5.4 mM hERG) the in vitro t1/2 doubled to 0.88 h.

Arylimidazoles derived from p-carboline 36 have also been described with activity assessed in a binding assay to rNav1.2 [60]. Compounds were further evaluated in a functional assay in blocking the cytotoxic effects of veratridine, a sodium channel opener, in SH-SY5Y neuroblastoma cells. The SAR showed that the R1 position required a lipohphilic group to maintain activity. For example, when the n-hexyl of 37 (IC50 = 16 nM) was shortened to a methyl, 38, the potency decreased to an IC50 of 1460 nM in the binding assay.

Furthermore, R2 seemed to tolerate a variety of groups but the potency was dependant on the size of the lipophilic group in R1. For example, 39, IC50 = 518 nM, improves potency to 146 nM by increasing the size of the lipophilic group at R1 as in 40. A further increase was realized by substituting the fluorine at R2 with a tBu group to provide 41 with an IC50 = 30 nM. No other sodium channel selectivity data or biophysical characterization were provided.

A series of non-selective benzimidazoles, exemplified by 42 has been described. In addition to the amide, ureas are exemplified as well as indole amides and they are claimed to be blockers of sodium and CaV2.2 channels [61].

Recently, three related series of quinazolines [62] and pyrimidines [63,64], 43, 44, 45, claimed as voltage-gated ion channel blockers for chronic and neuropathic pain with screening assays were described for Nav1.2, Nav1.3 and CaV2.2. No other biological data or selectivity data were presented, and therefore it is difficult to determine their potential as blockers.

Aminothiazolesulfonamide phenyl amides, 46, with a number of carbamates and ureas exemplified have been claimed as sodium and calcium channel blockers for chronic and neuropathic pain with screeing assays described for Nav1.2, Nav1.3 and CaV2.2 [65,66].

A number of novel series have been identified by screening against Nav1.8. Amino amide (47) derivatives [67] and substituted benzyloxy phenyls 48 where the amide has been removed [68], and azacyclic amides 49 (IC50 = 190 nM) [69] were identified by screening in a SH-SY5Y neuroblastoma cell line stably expressing human Nav1.8 on a FLIPR platform.

Other series that have been claimed as Nav1.8 blockers include pyrazolopyrimi-dines 50, pyrazoles 51 and piperidines 52, all of which were identified in a flux assay [70-73]. Selectivity data were not provided.

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