Dewar Pyridines: Conformationally Programmable Piperidine Isosteres

25 May 2023, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


Bioisosteric replacement is an indispensable tool in the medicinal chemist’s arsenal to strike a fine balance in multiparameter optimization campaigns and to deliver the best molecules for further preclinical development. The piperidine heterocycle, a dominant fragment in drug discovery, is often targeted for such replacement in attempts to improve potency and ADME (absorption, distribution, metabolism, excretion) profile. In this manuscript we explore 4H-Dewar pyridines (4H-DP) as rigid programmable isosteres of equatorially and elusive axially substituted piperidines. These fragments are readily accessible via pyridine dearomatization without the need for expensive catalysts and reagents. A wide spectrum of available reactivities enables incorporation of 4H-DP in various structural contexts. Exit vector analysis (EVA) underscores topological similarity with the parent piperidine as well as complementarity with the previously reported bioisosteres.


Dewar pyridines
drug design

Supplementary materials

Supporting Information
Experimental Procedures and Characterization of Compounds


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