Rational design, efficient syntheses and biological evaluation of N,N′-symmetrically bis-substituted butylimidazole analogs as a new class of potent Angiotensin II receptor blockers

A series of symmetrically bis-substituted imidazole analogs bearing at the N-1 and N-3 two biphenyl moieties ortho substituted either with tetrazole or carboxylate functional groups was designed based on docking studies and utilizing for the first time an extra hydrophobic binding cleft of AT1 receptor. The synthesized analogs were evaluated for their in vitro antagonistic activities (pA2 values) and binding affinities (–logIC50 values) to the Angiotensin II AT1 receptor. Among them, the potassium (–logIC50 = 9.04) and the sodium (–logIC50 = 8.54) salts of 4-butyl-N,N′-bis{[2′-(2H-tetrazol-5-yl)biphenyl-4-yl]methyl}imidazolium bromide (12a and 12b, respectively) as well as its free acid 11 (–logIC50 = 9.46) and the 4-butyl-2-hydroxymethyl-N,N′-bis{[2′-(2H-tetrazol-5-yl)biphenyl-4-yl]methyl}imidazolium bromide (14) (–logIC50 = 8.37, pA2 = 8.58) showed high binding affinity to the AT1 receptor and high antagonistic activity (potency). The potency was similar or even superior to that of Losartan (–logIC50 = 8.25, pA2 = 8.25). On the contrary, 2-butyl-N,N′-bis{[2′-[2H-tetrazol-5-yl)]biphenyl-4-yl]methyl}imidazolium bromide (27) (–logIC50 = 5.77) and 2-butyl-4-chloro-5-hydroxymethyl-N,N′-bis{[2′-[2H-tetrazol-5-yl)]biphenyl-4-yl]methyl}imidazolium bromide (30) (–logIC50 = 6.38) displayed very low binding affinity indicating that the orientation of the n-butyl group is of primary importance. Docking studies of the representative highly active 12b clearly showed that this molecule has an extra hydrophobic binding feature compared to prototype drug Losartan and it fits to the extra hydrophobic cavity. These results may contribute to the discovery and development of a new class of biologically active molecules through bis-alkylation of the imidazole ring by a convenient and cost effective synthetic strategy

AT1 antagonists: a patent review (2008 - 2012)

Introduction: For two decades a class of pharmaceutical molecules with proved beneficial therapeutic properties, especially in hypertension, has been introduced in the market aiming to specifically prevent the detrimental effects of the peptide hormone Angiotensin II at the AT1 receptor. The prototype of this class was losartan and based on its structure, several drugs were launched and also called 'Sartans'. New structural features on these molecules can provide multi-target properties in the RAS or other systems. New methodologies were developed for the treatment of hypertension utilizing either AT1 antagonists alone or as cocktails. Areas covered: In this review article, authors aim to cover information provided by patents of the years 2008 - 2012. The rationale of writing this review article is to cover the most important patents which can forward the field with new important discoveries. Expert opinion: From the patent investigation it is clear that new areas on the subject are still offered for new discoveries. New structural features can be still considered in the synthetic compounds that can advance the knowledge and beneficial effects on diseases related to Angiotensin II and AT1 receptor. There is era also for new formulations (i.e., cyclodextrins, polymers and liposomes). The multitarget approach can be further strengthened and more combinations can be sought in the rational drug design for seeking cocktails. Furthermore, the revealing of the complexity of the RAS offers new avenues for novel targets and this must not be overlooked

Design, Synthesis, and Molecular Modeling of a Novel Amide-Linked Cyclic GnRH Analogue Cyclo(4-9)[Lys4,d-Trp6,Glu9]GnRH: Stimulation of Gonadotropin Gene Expression

This report describes the rational design, synthesis, and pharmacological properties of an amide-linked cyclic analogue of gonadotropin-releasing hormone (GnRH) namely Cyclo(4−9)[Lys4,d-Trp6,Glu9]GnRH. The conformationally restricted analogue is characterized by reduced flexibility of the peptide strand due to the introduction of a β-turn mimetic through 4,9 residue amide cyclization. The cyclic analogue was found to stimulate gonadotropin gene expression in the goldfish pituitary with similar potency compared to two native forms of GnRH. Simulation studies based on ROE connectivities in linear GnRH and potency of cyclic analogue supports the His2, Trp3, Tyr5 clustering considered important for triggering receptor activation

Facile and Efficient Syntheses of a Series of N-Benzyl and N-Biphenylmethyl Substituted Imidazole Derivatives Based on (E)-Urocanic acid, as Angiotensin II AT1 Receptor Blockers

molecule

Insights into AT₁ Receptor Activation through AngII Binding Studies

This study investigates the binding of angiotensin II (AngII) to the angiotensin II type 1 receptor (AT₁R), taking into consideration several known activation elements that have been observed for G-protein-coupled receptors (GPCRs). In order to determine the crucial interactions of AngII upon binding, several MD simulations were implemented using AngII conformations derived from experimental data (NMR ROEs) and <i>in silico</i> flexible docking methodologies. An additional goal was to simulate the induced activation mechanism and examine the already known structural rearrangements of GPCRs upon activation. Performing MD simulations to the AT₁R – AngII – lipids complex, a series of dynamic changes in the topology of AngII and the intracellular part of the receptor were observed. Overall, the present study proposes a complete binding profile of AngII to the AT₁R, as well as the key transitional elements of the receptor and the agonist peptide upon activation through NMR and <i>in silico</i> studies

Insights into AT₁ Receptor Activation through AngII Binding Studies

This study investigates the binding of angiotensin II (AngII) to the angiotensin II type 1 receptor (AT₁R), taking into consideration several known activation elements that have been observed for G-protein-coupled receptors (GPCRs). In order to determine the crucial interactions of AngII upon binding, several MD simulations were implemented using AngII conformations derived from experimental data (NMR ROEs) and <i>in silico</i> flexible docking methodologies. An additional goal was to simulate the induced activation mechanism and examine the already known structural rearrangements of GPCRs upon activation. Performing MD simulations to the AT₁R – AngII – lipids complex, a series of dynamic changes in the topology of AngII and the intracellular part of the receptor were observed. Overall, the present study proposes a complete binding profile of AngII to the AT₁R, as well as the key transitional elements of the receptor and the agonist peptide upon activation through NMR and <i>in silico</i> studies

Insights into AT₁ Receptor Activation through AngII Binding Studies

This study investigates the binding of angiotensin II (AngII) to the angiotensin II type 1 receptor (AT₁R), taking into consideration several known activation elements that have been observed for G-protein-coupled receptors (GPCRs). In order to determine the crucial interactions of AngII upon binding, several MD simulations were implemented using AngII conformations derived from experimental data (NMR ROEs) and <i>in silico</i> flexible docking methodologies. An additional goal was to simulate the induced activation mechanism and examine the already known structural rearrangements of GPCRs upon activation. Performing MD simulations to the AT₁R – AngII – lipids complex, a series of dynamic changes in the topology of AngII and the intracellular part of the receptor were observed. Overall, the present study proposes a complete binding profile of AngII to the AT₁R, as well as the key transitional elements of the receptor and the agonist peptide upon activation through NMR and <i>in silico</i> studies