NeurAxon (Canada)

Herein, we report a high-yielding nickel/photoredox-catalyzed amidine arylation method that accommodates a wide range of aryl halides and amidines. The method exhibits good functional group tolerance enabling its successful application to both simple substrates and late-stage functionalization experiments. Mechanistic studies revealed the pivotal role of an in situ generated triazine co-catalyst. This information allowed us to further optimize the protocol, achieving faster reaction rates, milder conditions, and most importantly the substrate scope was expanded to sulfonamides and primary amines as well.

A family of different 3,5-disubstituted indole derivatives having 6-membered rings were designed, synthesized, and demonstrated inhibition of human nitric oxide synthase (NOS) with norepinephrine reuptake inhibitory activity (NERI). The structure-activity relationship (SAR) within the cyclohexane ring showed the cis-isomers to be more potent for neuronal NOS and selective over endothelial NOS compared to their trans-counterparts. Compounds, such as cis-(+)-37, exhibited dual nNOS and NET inhibition (IC(50) of 0.56 and 1.0 μM, respectively) and excellent selectivity (88-fold and 12-fold) over eNOS and iNOS, respectively. The lead compound (cis-(+)-37) showed lack of any direct vasoconstriction or inhibition of ACh-mediated vasorelaxation in isolated human coronary arteries. Additionally, cis-(+)-37 was effective at reversing both allodynia and thermal hyperalgesia in a standard Chung (spinal nerve ligation) rat neuropathic pain model. Overall, the data suggest that cis-(+)-37 is a promising dual action development candidate having therapeutic potential for the treatment of neuropathic pain.