Synthesis of 5-, 6- and 7-substituted-2-aminoquinolines as SH3 domain ligands

Chreifi

et al. 2017

Neuronal nitric oxide synthase (nNOS) inhibition is a promising strategy to treat neurodegenerative disorders, but development of nNOS inhibitors is often hindered by poor pharmacokinetics. We previously developed a class of membrane-permeable 2-aminoquinoline inhibitors and later rearranged the scaffold to decrease off-target binding. However, the resulting compounds had decreased permeability, low human nNOS activity, and low selectivity versus human eNOS. In this study, 5-substituted phenyl ether-linked aminoquinolines and derivatives were synthesized and assayed against purified NOS isoforms. 5-Cyano compounds are especially potent and selective rat and human nNOS inhibitors. Activity and selectivity are mediated by the binding of the cyano group to a new auxiliary pocket in nNOS. Potency was enhanced by methylation of the quinoline and by introduction of simple chiral moieties, resulting in a combination of hydrophobic and auxiliary pocket effects that yielded high (∼500-fold) n/e selectivity. Importantly, Caco-2 assay also revealed improved membrane permeability over previous compounds.

Section: Chemistrymentioning

confidence: 99%

Nitrile in the Hole: Discovery of a Small Auxiliary Pocket in Neuronal Nitric Oxide Synthase Leading to the Development of Potent and Selective 2-Aminoquinoline Inhibitors

Chreifi

et al. 2017

“…Previously, 7-substituted-2-aminoquinolines were prepared via readily accessible chloroquinoline 23 18, 29 (Scheme 1) by performing a Korodi amidation 30 to produce 2-acetamidoquinoline 25 . Unfortunately, this procedure gives irreproducible yields and is not readily amenable to scale-up.…”

Section: Chemistrymentioning

confidence: 99%

Phenyl Ether- and Aniline-Containing 2-Aminoquinolines as Potent and Selective Inhibitors of Neuronal Nitric Oxide Synthase

Pensa

et al. 2015

Excess nitric oxide (NO) produced by neuronal nitric oxide synthase (nNOS) is implicated in neurodegenerative disorders. As a result, inhibition of nNOS and reduction of NO levels is desirable therapeutically, but many nNOS inhibitors are poorly bioavailable. Promising members of our previously reported 2-aminoquinoline class of nNOS inhibitors, although orally bioavailable and brain-penetrant, suffer from unfavorable off-target binding to other CNS receptors, and they resemble known promiscuous binders. Rearranged phenyl ether- and aniline-linked 2-aminoquinoline derivatives were therefore designed to a) disrupt the promiscuous binding pharmacophore and diminish off-target interactions, and b) preserve potency, isoform selectivity, and cell permeability. A series of these compounds was synthesized and tested against purified nNOS, endothelial NOS (eNOS), and inducible NOS (iNOS) enzymes. One compound, 20, displayed high potency, selectivity, and good human nNOS inhibition, and retained some permeability in a Caco-2 assay. Most promisingly, CNS receptor counterscreening revealed this rearranged scaffold significantly reduces off-target binding.

“…39,40 Compound 17 was subsequently treated with an excess of aluminum chloride in chlorobenzene to affect cyclization and concomitant cleavage of the C-aryl bond to yield the carbostyril 18 as a mixture of the 7-isomer 18a (major) and 5-isomer 18b (minor). 39−41 The isomers were not separated at this stage but were converted into the 2-chloroquinolines 19a and 19b ; the unwanted 5-isomer 19b was removed by fractional crystallization.…”

Section: Chemistrymentioning

confidence: 99%

“…39−41 The isomers were not separated at this stage but were converted into the 2-chloroquinolines 19a and 19b ; the unwanted 5-isomer 19b was removed by fractional crystallization. 41 Pure 19a was converted into 2-acetamidoquinoline 20 by the method of Kóródi, 42 and free-radical bromination 40 afforded versatile intermediate 21 (Scheme 1). …”

Section: Chemistrymentioning

confidence: 99%

See 1 more Smart Citation

Simplified 2-Aminoquinoline-Based Scaffold for Potent and Selective Neuronal Nitric Oxide Synthase Inhibition

Chreifi

et al. 2014

Since high levels of nitric oxide (NO) are implicated in neurodegenerative disorders, inhibition of the neuronal isoform of nitric oxide synthase (nNOS) and reduction of NO levels are therapeutically desirable. Nonetheless, many nNOS inhibitors mimic l-arginine and are poorly bioavailable. 2-Aminoquinoline-based scaffolds were designed with the hope that they could (a) mimic aminopyridines as potent, isoform-selective arginine isosteres and (b) possess chemical properties more conducive to oral bioavailability and CNS penetration. A series of these compounds was synthesized and assayed against purified nNOS enzymes, endothelial NOS (eNOS), and inducible NOS (iNOS). Several compounds built on a 7-substituted 2-aminoquinoline core are potent and isoform-selective; X-ray crystallography indicates that aminoquinolines exert inhibitory effects by mimicking substrate interactions with the conserved active site glutamate residue. The most potent and selective compounds, 7 and 15, were tested in a Caco-2 assay and showed good permeability and low efflux, suggesting high potential for oral bioavailability.