We have observed a high correlation between the intermolecular interaction energy (Einter) calculated for HIV-1 protease inhibitor complexes and the observed in vitro enzyme inhibition. A training set of 33 inhibitors containing modifications in the P1' and P2' positions was used to develop a regression equation which relates Einter and pIC50. This correlation was subsequently employed to successfully predict the activity of proposed HIV-1 protease inhibitors in advance of synthesis in a structure-based design program. This included a precursor, 47, to the current phase II clinical candidate, L-735,524 (51). The development of the correlation, its applications, and its limitations are discussed, and the force field (MM2X) and host molecular mechanics program (OPTIMOL) used in this work are described.

Arylboronic acids have been found to couple efficiently with 5-bromonicotinates to yield 5-arylnicotinates. The reaction is considerably more sensitive to steric inhibition in the arylboronic acid component than in the pyridyl bromide 4. The dianion salt of the boronic acid is implicated as the reactive intermediate responsible for the facile coupling reaction. Pure arylboronic acids are best prepared by using triisopropyl borate as the transmetalating agent.

An efficient and mild method for alkoxycarbonylation of amines is described, utilizing commercially available N,N'-disuccinimidyl carbonate.

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