Nuclear magnetic resonance studies and conformations of bicyclic inhibitors of angiotensin-converting enzyme. Part 1. Octahydropyridazo[1,2-a]-pyridizanediones as models for alanylproline and captopril

Abstract

The conformations of several substituted octahydropyridazo[1,2-a]pyridazinediones have been determined, using n.m.r. spectroscopy and X-ray diffraction, to assess the suitability of the constrained ring system to hold the enzyme binding moieties (pharmacophores) in the optimum three-dimensional configuration. The bicyclic ring system is shown to be rigid in solution, anchored by the axial carboxy group in the reduced pyridazine ring. In all cases a rigid chair–twist boat conformation is found, independent of the substituents in the dione ring. This system is not optimal for binding, as it mimics a relatively high-energy conformation of alanylproline.