Trandolapril, an angiotensin-converting enzyme (ACE) inhibitor, undergoes two-state exchange in organic solvents arising from cis-trans isomerization around a N-C bond. A previous NMR study reported different equilibrium constants depending on which 1H nuclei were used for analysis. Such variations have been attributed to experimental error but require experimental resolution. In this study, we developed a new method for measuring cross-peak volumes based on a projection technique and applied the method to a series of two-dimensional 1H-13C HSQC spectra of trandolapril, acquired using the time-zero HSQC (HSQC0) scheme. The Proj-Vol method yielded consistent equilibrium constant values across multiple 1H nuclei, demonstrating that trandolapril has a single equilibrium constant, consistent with its single exchange mechanism. The Proj-Vol method is based on constructing 1D 13C projections of narrow rectangular regions around the cross-peaks. The use of 1D projection provides several advantages, including fewer fitting parameters and the elimination of the need to consider peak splitting due to 1H homonuclear J-couplings. It also offers other useful benefits, such as a narrower projection box size to reduce the contributions of other diagonally overlapping cross-peaks in 2D HSQC spectra, the improved signal-to-noise ratio of projection spectra by slice summation, and the cancellation of dispersion components caused by spectral misphasing in the 1H dimension. These advantages and benefits increase the accuracy of cross-peak volume determination in 2D HSQC spectra, compared with existing methods that directly fit 2D cross-peak shapes.
Kohda et al. (Mon,) studied this question.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: