Targeting the Zinc Metalloproteinase Superfamily in the CNS: Medicinal Chemistry Strategies To Optimize Selectivity, Pharmacokinetics, and Blood–Brain Barrier Permeability

Abstract The zinc metalloproteinase superfamily [matrix metalloproteinases (MMPs), a disintegrin and metalloproteinases (ADAMs), and ADAMs with thrombospondin motifs (ADAMTSs)] represents a high-value yet elusive therapeutic target for peripheral disorders and central nervous system (CNS) pathologies. Historically, active-site-centric drug discovery using potent zinc-binding groups (ZBGs) has achieved subnanomolar potency but suffered from severe cross-reactivity and poor pharmacokinetics, leading to widespread clinical failures. In particular, medicinal chemistry must simultaneously optimize enzyme selectivity, metabolic stability, and blood–brain barrier permeability to revitalize this target class for the highly restricted CNS chemical space. This work deconstructs the structural evolution of small-molecule inhibitors from a rigorous medicinal chemistry perspective. Additionally, we highlight the emerging paradigm of leveraging DNA-encoded chemical libraries (DEL) to efficiently select basic, non-ZBG scaffolds that bypass classical chelation pitfalls. Furthermore, through in silico profiling and CNS multiparameter optimization (CNS MPO) scoring, we demonstrate how targeted structural truncation can successfully refine initially oversized DEL hits into highly optimized, CNS-compatible templates. Finally, this review provides a technology-driven roadmap for navigating multiparameter optimization to achieve CNS-targeted metalloproteinase drug discovery.