Modular Synthetic Platform for the Elaboration of Fragments in Three Dimensions for Fragment-Based Drug Discovery.

ABSTRACT: Fragment-based drug discovery (FBDD) is a key strategy employed in the hit-to-lead phase of pharmaceutical development. The rate-limiting step of this process is often identifying and optimizing synthetic chemistry suitable for fragment elaboration, especially in three dimensions (3-D). To address this limitation, we herein present a modular platform for the systematic and programmable elaboration of two-dimensional (2-D) fragment hits into lead-like 3-D compounds, utilizing nine bifunctional building blocks that explore a range of vectors in 3-D. The building blocks comprise (i) rigid sp³-rich bicyclic cyclopropane-based structures to fix the vectors and (ii) two synthetic handles─a protected cyclic amine and a cyclopropyl N-methyliminodiacetic acid (MIDA) boronate. To v

SUBMITTER: Gomez-Angel AR 

PROVIDER: S-EPMC12356528 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature