Furazans in Medicinal Chemistry

Abstract

Incorporation of heterocycles into drug molecules can enhance physical properties and biological activity. A variety of heterocyclic groups is available to medicinal chemists, many of which have been reviewed in detail elsewhere. Oxadiazoles are a class of heterocycle containing one oxygen and two nitrogen atoms, available in three isomeric forms. While the 1,2,4- and 1,3,4-oxadiazoles have seen widespread application in medicinal chemistry, 1,2,5-oxadiazoles (furazans) are less common. This Review provides a summary of the application of furazan-containing molecules in medicinal chemistry and drug development programs from analysis of both patent and academic literature. Emphasis is placed on programs that reached clinical or preclinical stages of development. The examples provided herein describe the pharmacology and biological activity of furazan derivatives with comparative data provided where possible for other heterocyclic groups and pharmacophores commonly used in medicinal chemistry.

Synthesis of 4‐Trifluoromethylated 1,3‐Butadienes via Palladium Catalyzed Heck Reaction

“…In addition to aromatic amines, heterocyclic amines are very important because many important best‐selling drugs contain heterocyclic amine skeletons. [ 34‐35 ] Therefore, we also tested heterocyclic‐substituted enamides (Scheme 3). It is very encouraging that most of the pyridine‐substituted enamides can undergo this chemical transformation, the isolated yields of corresponding products were also good, and most importantly, the product E / Z ratio was always high (Scheme 3, — 4g ).…”

Bioisosteres of the Phenyl Ring: Recent Strategic Applications in Lead Optimization and Drug Design

“…It was recognized that the presence of multiple planar aryl rings was a potential contributing factor to the poor solubility properties since these features would favor close crystal packing and interfere with efficient dissolution. The strategy adopted to disrupt crystal packing was to truncate the benzo­[ c ]­[1,2,5]­oxadiazole ring to a single monosubstituted aromatic ring and to replace the benzoic acid element with a saturated isostere, which ultimately led to the identification of 47b as a clinical candidate. , In this series, only the trans -topography inherent to 47b was described, a function of the facile isomerization of the cis -isomer during saponification of the precursor ethyl ester. , In a phase 1 clinical trial, 47b was well absorbed in both normal healthy volunteers (NHVs) and patients, with both the AUC and C max exhibiting dose-proportionality following single oral doses that ranged from 0.5 to 25 mg in the fed state. The reproducible and predictable PK observed with 47b allowed the design of an escalating dosing regimen while minimizing C max and the associated nausea and vomiting.…”

“…The strategy adopted to disrupt crystal packing was to truncate the benzo[c] [1,2,5]oxadiazole ring to a single monosubstituted aromatic ring and to replace the benzoic acid element with a saturated isostere, which ultimately led to the identification of 47b as a clinical candidate. 109,110 In this series, only the transtopography inherent to 47b was described, a function of the facile isomerization of the cis-isomer during saponification of the precursor ethyl ester. 107,108 In a phase 1 clinical trial, 47b was well absorbed in both normal healthy volunteers (NHVs) and patients, with both the AUC and C max exhibiting doseproportionality following single oral doses that ranged from 0.5 to 25 mg in the fed state.…”

Furoxan Incorporation into C–H Bonds Enabling Nitrogen-Containing Functional Group Installation into the Same

“…Furoxan is a heterocyclic compound with weak aromaticity . Because furoxan is susceptible to ring-opening under various reaction conditions, C–C bond-forming reactions on the furoxan ring have been underdeveloped .…”