A complete characterization of the 3D properties of the CCR5 antagonist Vicriviroc

Vicriviroc is a piperazine-based CCR5 receptor antagonist, that showed better oral availability, potency, safety, and pharmacological properties than its precursor SCH-C, but whose development has been stopped. A full evaluation of the 3D properties of Vicriviroc was carried out, in order to achieve a complete knowledge of its conformational behavior and, consequently, identify the parameters necessary to design new, possibly better, analogs. A theoretical study of 1 was performed at the B3LYP/6-31G(d) level of calculation. Particular attention was focused on the conformational preferences of the piperazine and piperidine rings and on their inversion, with the obtainment of four conformational families characterized by different “through space contacts”, experimentally confirmed. High field NMR spectroscopy supported the computational results and assured the coexistence, in solution, of several conformations in equilibrium. Conversely, rotation around the N6-C6a and N3-C1” single bonds was shown to be difficult and determined, for both the bonds, a neat preference for one staggered conformations.