First-in-Class, Dual-Action, 3,5-Disubstituted Indole Derivatives Having Human Nitric Oxide Synthase (nNOS) and Norepinephrine Reuptake Inhibitory (NERI) Activity for the Treatment of Neuropathic Pain

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 <i>cis</i>-isomers to be more potent for neuronal NOS and selective over endothelial NOS compared to their <i>trans</i>-counterparts. Compounds, such as <i>cis</i>-(+)-<b>37</b>, exhibited dual nNOS and NET inhibition (IC₅₀ of 0.56 and 1.0 μM, respectively) and excellent selectivity (88-fold and 12-fold) over eNOS and iNOS, respectively. The lead compound (<i>cis</i>-(+)-<b>37</b>) showed lack of any direct vasoconstriction or inhibition of ACh-mediated vasorelaxation in isolated human coronary arteries. Additionally, <i>cis</i>-(+)-<b>37</b> 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 <i>cis</i>-(+)-<b>37</b> is a promising dual action development candidate having therapeutic potential for the treatment of neuropathic pain

Potent and Selective Double-Headed Thiophene-2-carboximidamide Inhibitors of Neuronal Nitric Oxide Synthase for the Treatment of Melanoma

Selective inhibitors of neuronal nitric oxide synthase (nNOS) are regarded as valuable and powerful agents with therapeutic potential for the treatment of chronic neurodegenerative pathologies and human melanoma. Here, we describe a novel hybrid strategy that combines the pharmacokinetically promising thiophene-2-carboximidamide fragment and structural features of our previously reported potent and selective aminopyridine inhibitors. Two inhibitors, 13 and 14, show low nanomolar inhibitory potency (Ki = 5 nM for nNOS) and good isoform selectivities (nNOS over eNOS [440- and 540-fold, respectively] and over iNOS [260- and 340-fold, respectively]). The crystal structures of these nNOS–inhibitor complexes reveal a new hot spot that explains the selectivity of 14 and why converting the secondary to tertiary amine leads to enhanced selectivity. More importantly, these compounds are the first highly potent and selective nNOS inhibitory agents that exhibit excellent in vitro efficacy in melanoma cell lines

Palladium-Catalyzed N-Monoarylation of Amidines and a One-Pot Synthesis of Quinazoline Derivatives

[Image: see text] A method for the Pd-catalyzed N-arylation of both aryl and alkyl amidines with a wide range of aryl bromides, chlorides, and triflates is described. The reactions proceed in short reaction times and with excellent selectivity for monoarylation. A one-pot synthesis of quinazoline derivatives, via addition of an aldehyde to the crude reaction mixture following Pd-catalyzed N-arylation, is also demonstrated