Oxadiazoles in medicinal chemistry.

Abstract:

:Oxadiazoles are five-membered heteroaromatic rings containing two carbons, two nitrogens, and one oxygen atom, and they exist in different regioisomeric forms. Oxadiazoles are frequently occurring motifs in druglike molecules, and they are often used with the intention of being bioisosteric replacements for ester and amide functionalities. The current study presents a systematic comparison of 1,2,4- and 1,3,4-oxadiazole matched pairs in the AstraZeneca compound collection. In virtually all cases, the 1,3,4-oxadiazole isomer shows an order of magnitude lower lipophilicity (log D), as compared to its isomeric partner. Significant differences are also observed with respect to metabolic stability, hERG inhibition, and aqueous solubility, favoring the 1,3,4-oxadiazole isomers. The difference in profile between the 1,2,4 and 1,3,4 regioisomers can be rationalized by their intrinsically different charge distributions (e.g., dipole moments). To facilitate the use of these heteroaromatic rings, novel synthetic routes for ready access of a broad spectrum of 1,3,4-oxadiazoles, under mild conditions, are described.

journal_name

J Med Chem

authors

Boström J,Hogner A,Llinàs A,Wellner E,Plowright AT

doi

10.1021/jm2013248

subject

Has Abstract

pub_date

2012-03-08 00:00:00

pages

1817-30

issue

5

eissn

0022-2623

issn

1520-4804

journal_volume

55

pub_type

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