Synthesis and enzymatic evaluation of 2- and 4-aminothiazole-based inhibitors of neuronal nitric oxide synthase

Abstract

SummaryHighly potent and selective inhibitors of neuronal nitric oxide synthase (nNOS) possessing a 2-aminopyridine group were recently designed and synthesized in our laboratory and were shown to have significant in vivo efficacy. In this work, analogs of our lead compound possessing 2- and 4-aminothiazole rings in place of the aminopyridine were synthesized. The less basic aminothiazole rings will be less protonated at physiological pH than the aminopyridine ring, and so the molecule will carry a lower net charge. This could lead to an increased ability to cross the blood-brain barrier thereby increasing the in vivo potency of these compounds. The 2-aminothiazole-based compound was less potent than the 2-aminopyridine-based analogue. 4-Aminothiazoles were unstable in water, undergoing tautomerization and hydrolysis to give inactive thiazolones.

Cs2CO3‐Promoted Direct N‐Alkylation: Highly Chemoselective Synthesis of N‐Alkylated Benzylamines and Anilines

“…Ethyl (4‐chlorobenzyl)glycinate (3p): Following the general procedure, the reaction of p ‐chlorobenzylamine ( 1c , 215 µL, 1.77 mmol), ethyl bromoacetate ( 2h , 98 µL, 0.88 mmol) and cesium carbonate (287 mg, 0.88 mmol) in anhydrous DMF (4.0 mL) at 25 °C for 24 h, afforded compound 3p as a colourless oil (124 mg, 62 %) after silica gel purification (CH 2 Cl 2 ). 1 H NMR (400 MHz, CDCl 3 ): δ = 1.28 (t, J = 7.1 Hz, 3 H), 1.89 (br.…”

Development of nitric oxide synthase inhibitors for neurodegeneration and neuropathic pain

“…Numerous studies were undertaken in attempt to improve the membrane permeation and bioavailability of pyrrolidinomethyl-2-aminopyridines, including alkyl chain fluorination, 115,116 the introduction of internal hydrogen-bonding groups, 117 lipophilic moieties and aromatic tails, 118 alkylation and conformational restriction, 119 the introduction of various prodrug moieties and the use of azides as amine surrogates, 120 replacement of the aminopyridine with a less basic aminothiazole, 121 and the replacement of amino linkages with amides and ethers. 108,122 Most of these approaches were met with diminished activity and selectivity relative to the parent compounds, were synthetically challenging, or did not improve BBB permeation.…”

Amine Functionalization through Sequential Quinone‐Catalyzed Oxidation/Nucleophilic Addition

“…With the optimized conditions for amine oxidation in hand, sequential oxidation/nucleophilic addition reactions were examined. These studies began by exploring the efficiency of in situ addition reactions by using the lithiated ketene imine derived from acetonitrile as the nucleophilic reaction partner in combination with a variety of imines generated through quinone‐promoted amine oxidation to deliver a series of β‐amino nitriles ( 17 , Table ). A wide range of benzylic amines was well tolerated under these conditions.…”

“…The aqueous layer was further extracted by using EtOAc (3 × 15 mL) and the combined organic layers were dried (Na 2 SO 4 ), filtered, and concentrated under reduced pressure. Flash chromatography on silica gel provided the desired nitriles ( 17a – 17m ) …”