title: Dynamic NMR study and theoretical calculations on the conformational exchange of valsartan and related compounds.
abstract: Valsartan (1), an antihypertensive drug of the sartan family, and three related compounds, 3-methyl-2-((2'-(1-methyl-1H-tetrazol-5-yl)biphenyl-4-ylmethyl) pentanoylamino)butyric acid (2), 3-isopropyl-6-propyl-4-(2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl) morpholine-2,5-dione (3), and 3-isopropyl-6-propyl-4-(4'-(1H-tetrazol-5-yl)biphenyl4-ylmethyl) morpholine-2,5-dione (4), were studied by nuclear magnetic resonance (NMR) spectroscopy. Assignment of (1)H and (13)C NMR resonances for the compounds were completed using COSY, HSQC and HMBC techniques. It was found that each of the compounds 1, 2, and 4 had two sets of (1)H and (13)C resonances, suggesting the presence of two conformers in solution. Based on NOESY experiments at different temperatures, thermodynamic parameters of the conformational exchange process were deduced for these compounds. The exchange barrier was found to be 17.9 +/- 0.7, 18.5 +/- 0.8, and 17.7 +/- 0.6 kcal mol(-1) with the corresponding free energy difference (DeltaG) of 0.32 +/- 0.04, 0.23 +/- 0.01, and 0.13 +/- 0.04 kcal mol(-1) for 1, 2, and 4, respectively, at 298 K. Two conformations of valsartan were elucidated by NMR spectroscopy and quantum chemistry calculation. The results showed that two conformers of valsartan interchange via rotation about the C(O)--N bond.
authors: Wuhan Center for Magnetic Resonance, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan, 430071, People's Republic of China.
authors: Fang
authors: F
authors: Li
authors: Huiting
authors: H
authors: Zhang
authors: Ling
authors: L
authors: Jiang
authors: Weinong
authors: W
authors: Zhang
authors: Jing
authors: J
authors: Nie
authors: Yuqi
authors: Y
authors: Feng
authors: Minghui
authors: M
authors: Yang
authors: Maili
authors: M
authors: Liu
mesh_terms: D000959:Antihypertensive Agents / Q000737:chemistry*; D002087:Butyrates / Q000737:chemistry; D007700:Kinetics; D008958:Models, Molecular; D008968:Molecular Conformation; D009025:Morpholines / Q000737:chemistry; D019906:Nuclear Magnetic Resonance, Biomolecular / Q000379:methods*; D011789:Quantum Theory; D013777:Tetrazoles / Q000737:chemistry*; D013816:Thermodynamics; D014633:Valine / Q000031:analogs & derivatives* / Q000737:chemistry; D000068756:Valsartan
chemical_list: D000959:Antihypertensive Agents; D002087:Butyrates; D009025:Morpholines; D013777:Tetrazoles; D000068756:Valsartan; D014633:Valine