Molecular structure of antihypertensive drug perindopril, its active metabolite perindoprilat and impurity F

The molecular structure of the antihypertensive drug perindopril (2S,3aS,7aS)-1-[(2S)-2-[[(2S)-1-ethoxy1-oxopentan-2-yl]amino]propanoyl]-2,3,3a,4,5,6,7,7a-octahydroindole-2 carboxylic acid), its active metabolite perindoprilat ((2S,3aS,7a5)-1-[(2S)-2-[ [(2S)-1-carboxybutyl]aminolpropanoy1]-2,3,3a,4,5,6,7, 7a-octahydroindole-2-carboxylic acid), and impurity F (ethyl (2S)-2((3S,5aS,9aS,10aS)-3-methyl-1,4dioxodecahydropyrazino[1,2-a]indol-2(1H)-yl) pentanoate) has been investigated using B3LYP/ 6-31g(d) and B3LYP/6-311+g(d,p) model chemistry. It has been found that solid state conformations of perindoprilat occur close to, but not actually at minima on the computed gas-phase potential energy surfaces. Both, neutral and zwitterionic structures of perindopril and perindoprilat have been investigated. Relative stability of individual ionized species of this drug has been determined. Water has a remarkable effect on the geometry of the perindopril species studied. (C) 2012 Elsevier B.V. All rights reserved.