Unique structure-activity relationship for 4-isoxazolyl-1,4-dihydropyridines

Gerald W. Zamponi, Stephanie C. Stotz, Richard J. Staples, Tina M. Andro, Jared K. Nelson, Victoria Hulubei, Alex Blumenfeld, Nicholas R. Natale

Research output: Contribution to journalArticlepeer-review

Abstract

A series of 4-isoxazolyl-1,4-dihydropyridines (IDs) were prepared and characterized, and their interaction with the calcium channel was studied by patch clamp analysis. The structureactivity relationship (SAR) that emerges is distinct from the 4-aryldihydropyridines (DHPs), and affinity increases dramatically at higher holding potentials. Thus, among the 3′-arylisoxazolyl analogues p-Br > p-Cl ≫ p-F, and p-Cl > m-Cl > o-Cl ≫ o-MeO. Four of the analogues were examined by single-crystal X-ray diffractometry, and all were found to adopt an O-exo conformation in the solid state. The calculated barrier to rotation, however, suggests that rotation about the juncture between the heterocyclic rings is plausible under physiological conditions. A variable-temperature NMR study confirmed the computation. With Striessnig's computational sequence homologation procedure, a working hypothesis was derived from the data that explains the unique SAR for IDs.

Original languageEnglish
Pages (from-to)87-96
Number of pages10
JournalJournal of Medicinal Chemistry
Volume46
Issue number1
DOIs
StatePublished - Jan 2 2003

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