Conformation and bioactivity. Design and discovery of novel antihypertensive drugs.

Peptidomimitism is applied to the medicinal chemistry in order to synthesize drugs that devoid of the disadvantages of peptides. AT1 antagonists constitute a new generation of drugs for the treatment of hypertension designed and synthesized to mimic the C-terminal segment of Angiotensin II and to block its binding action on AT1 receptor. An effort was made to understand the molecular basis of hypertension by studying the conformational analysis of Ang II and its derivatives as well as the AT1 antagonists belonging to SARTANs class of molecules. Such studies offer the possibility to reveal the stereoelectronic factors responsible for bioactivity of AT1 antagonists and to design and synthesize new analogs. An example will be given which proves that drugs with better pharmacological and financial profiles may arise based on this rational design.

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).

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.

The novel amide linked Angiotensin II (ANG II) cyclic analogue cyclo(3, 5) -[Sar(1)-Lys(3)-Glu(5)-Ile(8)] ANG II (18) has been designed, synthesized and bioassayed in anesthetized rabbits. The constrained cyclic analogue with a lactam amide bridge linking a Lys-Glu pair at positions 3 and 5 and possessing Ile at position 8, was synthesized by solution procedure using the maximum protection strategy. This analogue was found to be inhibitor of Angiotensin II. NMR spectroscopy coupled with computational analysis showed clustering between the side chains of the key aminoacids Tyr(4)-His(6)-Ile(8) similar to that observed with ANG II. The obtained data show that only pi*--pi* interactions observed in ANG II or its superagonist Sar(1) [ANG II] are missing. Therefore, it can be concluded that these interactions are essential for agonist activity. Conformational analysis comparisons between AT(1) antagonists losartan, eprosartan and irbesartan with C-terminal segment of cyclic compound 18 revealed structural similarities.