Accessing a Medicinal-Chemistry-Relevant Chemical Space with sp²–sp³ Hybrid Heterocyclic Fragments

Dedicated to our co-founder Prof. Erick Carreira

Abstract

Target-first drug discovery relies heavily on protein structure information, which severely limits its application. In recent years, fragment-based drug Design (FBDD) has been identified as an alternative solution, where screening of smaller molecules for lower affinity allowed the use of focused libraries with a higher hit rate. It is shown that coupling an sp²-rich heteroaromatic group with a monofunctional sp³-rich core gives fragments (186 examples) with advantageous physical-chemical properties, covering a chemical space often neglected in traditional libraries.

Key words

fragment-based drug design - azetidine - oxetane - medicinal chemistry - aqueous solubility - logP

Publication History

Received: 15 April 2024

Accepted after revision: 08 August 2024

Article published online:
09 September 2024

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