Pharmacophore-Based Design of Phenyl-[hydroxycyclohexyl] Cycloalkyl-Carboxamide Mitofusin Activators with Improved Neuronal Activity

Xiawei Dang, Sidney B. Williams, Sriram Devanathan, Antonietta Franco, Lijun Fu, Peter R. Bernstein, Daniel Walters, Gerald W. Dorn

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Mitochondrial fragmentation from defective fusion or unopposed fission contributes to many neurodegenerative diseases. Small molecule mitofusin activators reverse mitochondrial fragmentation in vitro, promising a novel therapeutic approach. The first-in-class mitofusin activator, 2, has a short plasma t1/2 and limited neurological system bioavailability, conferring "burst activation". Here, pharmacophore-based rational redesign generated analogues of 2 incorporating cycloalkyl linker groups. A cyclopropyl-containing linker, 5, improved plasma and brain t1/2, increased nervous system bioavailability, and prolonged neuron pharmacodynamic effects. Functional and single-crystal X-ray diffraction studies of stereoisomeric analogues of 5 containing sulfur as a "heavy atom", 14A and 14B, showed that 5 biological activity resides in the trans-R/R configuration, 5B. Structural analysis revealed stereoselective interactions of 5 associated with its mimicry of MFN2 Val372, Met376, and His380 side chains. Modification of murine ALS phenotypes in vitro and in vivo supports advancement of 5B for neurological conditions that may benefit from sustained mitofusin activation.

Original languageEnglish
Pages (from-to)12506-12524
Number of pages19
JournalJournal of Medicinal Chemistry
Volume64
Issue number17
DOIs
StatePublished - Sep 9 2021

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