Conformational and biological studies for a pair of novel synthetic AT1 antagonists: stereoelectronic requirements for antihypertensive efficacy.

One of the major systems which interferes with the disease of hypertension, is the Renin Angiotensin Aldosterone System (RAS). The octapeptide hormone angiotensin II is the active product of RAS which causes vasoconstriction when binds to the AT(1) receptor. In the last years, there has been a development of drugs which block the Angiotensin II from binding the AT(1) receptor and are called AT(1) antagonists. In an effort to comprehend their stereoelectronic features, a study has been initiated to compare the conformational properties of drugs already marketed for the treatment of hypertension and others which are designed and synthesized in our laboratory possessing structural characteristics necessary for antihypertensive activity. In this study, two synthetic non-peptide AT(1) antagonists, are structurally elucidated and their conformational properties and bioactivity are compared to the prototype and first approved drug of this category in the market; losartan (trade name: COZAAR).

[1]  T Mavromoustakos,et al.  An effort to understand the molecular basis of hypertension through the study of conformational analysis of losartan and sarmesin using a combination of nuclear magnetic resonance spectroscopy and theoretical calculations. , 1999, Journal of medicinal chemistry.

[2]  T Mavromoustakos,et al.  Synthesis and study of a cyclic angiotensin II antagonist analogue reveals the role of pi*--pi* interactions in the C-terminal aromatic residue for agonist activity and its structure resemblance with AT(1) non-peptide antagonists. , 2001, Bioorganic & medicinal chemistry.

[3]  M. Cicardi,et al.  Plasma bradykinin in angio-oedema , 1998, The Lancet.

[4]  B. Massie.  15 years of heart-failure trials: what have we learned? , 1998, The Lancet.

[5]  G. Bodenhausen,et al.  Natural abundance nitrogen-15 NMR by enhanced heteronuclear spectroscopy , 1980 .

[6]  Panagiotis Zoumpoulakis,et al.  Structure elucidation and conformational properties of eprosartan, a non peptide angiotensin II AT1 antagonist. , 2002, Journal of pharmaceutical and biomedical analysis.

[7]  P. D. de Leeuw,et al.  Non-peptide angiotensin type 1 receptor antagonists in the treatment of hypertension. , 1999, Journal of hypertension.

[8]  K. Wüthrich,et al.  Improved spectral resolution in cosy 1H NMR spectra of proteins via double quantum filtering. , 1983, Biochemical and biophysical research communications.

[9]  B. Stricker,et al.  ACE Inhibitor-Induced Angioedema , 1998, Drug safety.

[10]  W. Hall,et al.  Cough and Angioneurotic Edema Associated with Angiotensin-Converting Enzyme Inhibitor Therapy , 1992, Annals of Internal Medicine.

[11]  A. Overlack.  ACE Inhibitor-Induced Cough and Bronchospasm , 1996 .

[12]  P. Malini,et al.  Thromboxane antagonism and cough induced by angiotensin-converting-enzyme inhibitor , 1997, The Lancet.

[13]  Richard R. Ernst,et al.  Frequency offset effects and their elimination in NMR rotating-frame cross-relaxation spectroscopy , 1987 .

[14]  G. Vauquelin,et al.  Insurmountable angiotensin AT1 receptor antagonists: the role of tight antagonist binding. , 1999, European journal of pharmacology.