#Prototype 3 dr shaffeld series

4, 5, 6ДЄT 2R is predominantly expressed in fetal tissue, indicating its important role in fetal development.

2, 3 This receptor proved to be an enigmatic protein, which in recent years has emerged as a promising new drug target. However, in the late 1980s the first evidence of a second protein binding AngII appeared in the literature, the angiotensin II type 2 receptor (AT 2R). The angiotensin II type 1 receptor (AT 1R) was long believed to be the only mediator of the effects elicited by the endogenous AngII. the sartans) are well established therapeutics. 1 Hence, inhibitors of the two proteases important for formation of AngII (angiotensin converting enzyme, ACE, and renin) or compounds acting as antagonists at its receptor (i.вЂ‰e.

#Prototype 3 dr shaffeld series

Although a series of bioactive components are formed in RAAS, the octapeptide angiotensin II (AngII) is considered to constitute the major effector peptide. The reninвЂђangiotensinвЂђaldosterone system (RAAS) is wellвЂђknown for its role in fluidвЂђelectrolyte control and bloodвЂђpressure regulation there are several drugs on the market for the treatment of hypertension targeting proteins in RAAS. Based on data presented herein, a more adequate, tentative model of the binding modes of ligand analogues to the prototype AT 2R antagonist C38 is proposed, as deduced from docking redefined by molecular dynamic simulations.

In contrast to our previously reported findings, ligands with shorter carbamate alkyl chains only demonstrated slightly improved stability in microsomes. The majority of the compounds in the second series, including the most potent ligand, were inferior to C38 with regard to stability in both human and mouse microsomes.

The second series was comprised of new bicyclic derivatives, amongst which one ligand exhibited a fiveвЂђfold improved affinity to AT 2R as compared to C38. One compound in the first series was equipotent to C38 and showed similar kinetic solubility, and stability in both human and mouse liver microsomes. The first series explored the effects of adding small substituents to the phenyl ring of the known selective nonpeptide AT 2R antagonist C38, generating small but significant shifts in AT 2R affinity. Two series of compounds were synthesized and investigated. We here report on our continued studies of ligands binding to the promising drug target angiotensinвЂ…II typeвЂ…2 receptor (AT 2R).