RESUMEN
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.
Asunto(s)
Bloqueadores del Receptor Tipo 1 de Angiotensina II , Angiotensina II/análogos & derivados , Antihipertensivos/química , Diseño de Fármacos , 1-Sarcosina-8-Isoleucina Angiotensina II/análogos & derivados , 1-Sarcosina-8-Isoleucina Angiotensina II/química , Angiotensina II/química , Angiotensina II/farmacología , Antihipertensivos/síntesis química , Antihipertensivos/farmacología , Humanos , Hipertensión/tratamiento farmacológico , Losartán/análogos & derivados , Losartán/química , Espectroscopía de Resonancia Magnética , Conformación Molecular , Imitación Molecular , Péptidos/química , Péptidos/farmacología , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Angiotensina II/antagonistas & inhibidores , Angiotensina II/química , Angiotensina II/farmacología , Péptidos Cíclicos/química , Péptidos Cíclicos/farmacología , Tiofenos , Acrilatos/química , Acrilatos/farmacología , Angiotensina II/análogos & derivados , Angiotensina II/síntesis química , Animales , Antihipertensivos/química , Antihipertensivos/farmacología , Bioquímica/métodos , Compuestos de Bifenilo/química , Compuestos de Bifenilo/farmacología , Diseño de Fármacos , Imidazoles/química , Imidazoles/farmacología , Irbesartán , Losartán/química , Losartán/farmacología , Espectroscopía de Resonancia Magnética , Masculino , Modelos Moleculares , Péptidos Cíclicos/síntesis química , Conejos , Relación Estructura-Actividad , Tetrazoles/química , Tetrazoles/farmacologíaRESUMEN
The novel amide linked Angiotensin II potent cyclic analogue, c-[Sar1,Lys3,Glu5] ANG II 19 has been designed and synthesized in an attempt to test the aromatic ring clustering and the charge relay bioactive conformation we have recently suggested for ANG II. This constrained cyclic analogue was synthesized by connecting the Lys3 amino and Glu5 carboxyl side chain groups, and it was found to be potent in the rat uterus assay and in anesthetized rabbits. The central part of the molecule is fixed covalently in the conformation predicted according to the backbone bend conformational model proposed for Angiotensin II. The obtained results using a combination of 2D NMR, 1D NOE spectroscopy and molecular modeling revealed a similar Tyr4-Ile5-His6 bend, a His6-Pro7 trans configuration and a side chain aromatic ring cluster of the key aminoacids Tyr4, His6, Phe8 for c-[Sar1,Lys3,Glu5] ANG II as it has been found for ANG II (Matsoukas, J. H.; Hondrelis, J.; Keramida, M.; Mavromoustakos, T.; Markriyannis, A.; Yamdagni, R.; Wu, Q.; Moore, G. J. J. Biol. Chem. 1994, 269, 5303). Previous study of the conformational properties of the Angiotensin II type I antagonist [Hser(gamma-OMe)8] ANG II (Matsoukas, J. M.; Agelis, G.; Wahhab, A.; Hondrelis, J.; Panagiotopoulos. D.; Yamdagni, R.; Wu, Q.; Mavromoustakos, T.; Maia, H.; Ganter, R.; Moore, G. J. J. Med. Chem. 1995, 38, 4660) using 1-D NOE spectroscopy coupled with the present study of the same type of lead antagonist Sarilesin revealed that the Tyr4-Ile5-His6 bend, a conformational property found in Angiotensin II is not present in type I antagonists. The obtained results provide an important conformational difference between Angiotensin II agonists and type I antagonists. It appears that our synthetic attempt to further support our proposed model was successful and points out that the charge relay system and aromatic ring cluster are essential stereoelectronic features for Angiotensin II to exert its biological activity.