TY - JOUR
TI - Host-Guest Interactions between Candesartan and Its Prodrug Candesartan Cilexetil in Complex with 2-Hydroxypropyl-β-cyclodextrin: On the Biological Potency for Angiotensin II Antagonism
AU - D. Ntountaniotis, I. Andreadelis, T.F. Kellici, V. Karageorgos, G. Leonis, E. Christodoulou, S. Kiriakidi, J. Becker-Baldus, E.K. Stylos, M.V. Chatziathanasiadou, C.M. Chatzigiannis, D.E. Damalas, B. Aksoydan, U. Javrornik, G. Valsami, C. Glaubitz, S. Durdagi, N.S. Thomaidis, A. Kolocouris, J. Plavec, A.G. Tzakos, G. Liapakis, T. Mavromoustakos
JO - Molecular Pharmaceutics
PY - 2019
VL - 16
TODO - 3
SP - 1255-1271
PB - American Chemical Society (ACS)
SN - 1543-8384, 1543-8392
TODO - https://doi.org/10.1021/acs.molpharmaceut.8b01212
TODO - candesartan, candesartan cilexetil, 2-hydroxylpropyl-β-cyclodextrin, complex, biological efficacy
TODO - Renin−angiotensin aldosterone system inhibitors are for
25 a long time extensively used for the treatment of cardiovascular and renal
26 diseases. AT1 receptor blockers (ARBs or sartans) act as antihypertensive
27 drugs by blocking the octapeptide hormone Angiotensin II to stimulate
28 AT1 receptors. The antihypertensive drug candesartan (CAN) is the active
29 metabolite of candesartan cilexetil (Atacand, CC). Complexes of
30 candesartan and candesartan cilexetil with 2-hydroxylpropyl-β-cyclodextrin
31 (2-HP-β-CD) were characterized using high-resolution electrospray
32 ionization mass spectrometry and solid state 13C cross-polarization/
33 magic angle spinning nuclear magnetic resonance (CP/MAS NMR)
34 spectroscopy. The 13C CP/MAS results showed broad peaks especially in
35 the aromatic region, thus confirming the strong interactions between
36 cyclodextrin and drugs. This experimental evidence was in accordance with molecular dynamics simulations and quantum mechanical calculations. The
37 synthesized and characterized complexes were evaluated biologically in vitro. It was shown that as a result of CAN’s complexation, CAN exerts higher
38 antagonistic activity than CC. Therefore, a formulation of CC with 2-HP-β-CD is not indicated, while the formulation with CAN is promising and needs
39 further investigation. This intriguing result is justified by the binding free energy calculations, which predicted efficient CC binding to 2-HP-β-CD, and
40 thus, the molecule’s availability for release and action on the target is diminished. In contrast, CAN binding was not favored, and this may allow easy
41 release for the drug to exert its bioactivity.
ER -