Hydrophilic, Potent, and Selective 7-Substituted 2-Aminoquinolines as Improved Human Neuronal Nitric Oxide Synthase Inhibitors

Abstract

Neuronal nitric oxide synthase (nNOS) is a target for development of anti-neurodegenerative agents. Most nNOS inhibitors mimic L-arginine and have poor bioavailability. 2-Aminoquinolines showed promise as bioavailable nNOS inhibitors, but suffered from low human nNOS inhibition, low selectivity versus human eNOS, and significant binding to other CNS targets. We aimed to improve human nNOS potency and selectivity and reduce off-target binding by (a) truncating the original scaffold or (b) introducing a hydrophilic group to interrupt the lipophilic, promiscuous pharmacophore and promote interaction with human nNOS-specific His342. We synthesized both truncated and polar 2-aminoquinoline derivatives and assayed them against recombinant NOS enzymes. Although aniline and pyridine derivatives interact with His342, benzonitriles conferred the best rat and human nNOS inhibition. Both introduction of a hydrophobic substituent next to the cyano group and aminoquinoline methylation considerably improved isoform selectivity. Most importantly, these modifications preserved Caco-2 permeability and reduced off-target CNS binding.

First Contact: 7-Phenyl-2-Aminoquinolines, Potent and Selective Neuronal Nitric Oxide Synthase Inhibitors That Target an Isoform-Specific Aspartate

“…The quinoline portion of 5 mimics arginine and forms a bifurcated hydrogen bond system with the main-chain carbonyl of Trp587/Trp592 (rnNOS/hnNOS) and the side-chain carboxylate of Glu592/Glu602 (rnNOS/hnNOS). This is identical to the structural details observed for other nNOS inhibitors containing a 2-aminoquinoline. − All three crystal structures clearly reveal that the central phenyl ring resides between heme propionates A and D. In the hnNOS- 5 structure, the tail phenethylamine moiety makes a direct H-bond interaction with the H 4 B and propionate A, displacing the water there, while the rnNOS- 5 structure only makes H-bonding contacts with the carbonyl of the H 4 B and is unable to displace the water molecule bridging propionate A and H 4 B.…”

“…However, these compounds suffered from decreased Caco-2 permeability, low hnNOS activity, and similarly low hn/heNOS selectivity. Newer generations of inhibitors, such as 3 and 4 , improved upon their respective parent series by incorporating elements such as the quinoline 4-methyl group and cyano-containing tail moieties. , These compounds have greatly enhanced hnNOS potency, hn/heNOS selectivity, and improved cellular permeability and off-target profiles.…”

Creation of Novel Toxic Gas Surrogates and the Development of Safe and Facile Catalytic Reactions

“…Importantly, all reactions mentioned in this review using toxic gas surrogates were conducted without the use of an external source of toxic gas or special pressure-resistant apparatus, rendering their experimental protocols significantly simpler and more practical than those of conventional reactions using pressurized gases. In addition, since some CO surrogates developed in our laboratory are now commercially available at reasonable prices, 104) they have begun to be applied in the fields of medicinal chemistry, 105,106) total syntheses of natural bioactive compounds, 107,108) and flow chemistry. 109,110) For the development of truly useful reactions, the practical aspects of the organic reactions in question need to be considered during their development and application.…”

Access to C5-Alkylated Indolines/Indoles via Michael-Type Friedel–Crafts Alkylation Using Aryl-Nitroolefins

“…IR (CH 2 Cl 2 , cm −1 ): 2917,1617,1555,1438,1417,1327,1236,1068,968,808,798 (E)-1,2,3-Trimethoxy-5-(2-nitrovinyl)benzene (11h). 44 Compound 11h was obtained using GP2. Column chromatography (EtOAc/hexane (3:7)) gave the product as yellow crystals (1.04 g, 85% yield; mp 144−145 °C (CH 2 Cl 2 /hexane)).…”