An efficient synthesis of a rationally designed 1,5 disubstituted imidazole AT(1) Angiotensin II receptor antagonist: reorientation of imidazole pharmacophore groups in losartan reserves high receptor affinity and confirms docking studies

作者：Agelis George^*; Roumelioti Panagiota; Resvani Amalia; Durdagi Serdar; Androutsou Maria Eleni; Kelaidonis Konstantinos; Vlahakos Demetrios; Mavromoustakos Thomas; Matsoukas John

来源：Journal of Computer-Aided Molecular Design, 2010, 24(9): 749-758.

DOI：10.1007/s10822-010-9371-3

• Angiotensin II receptor antagonist
• Losartan
• Molecular modeling
• Docking theoretical calculations
• NMR spectroscopy

A new 1,5 disubstituted imidazole AT(1) Angiotensin II (AII) receptor antagonist related to losartan with reversion of butyl and hydroxymethyl groups at the 2-, 5-positions of the imidazole ring was synthesized and evaluated for its antagonist activity (V8). In vitro results indicated that the reorientation of butyl and hydroxymethyl groups on the imidazole template of losartan retained high binding affinity to the AT(1) receptor concluding that the spacing of the substituents at the 2,5- positions is of primary importance. The docking studies are confirmed by binding assay results which clearly show a comparable binding score of the designed compound V8 with that of the prototype losartan. An efficient, regioselective and cost effective synthesis renders the new compound as an attractive candidate for advanced toxicological evaluation and a drug against hypertension.

• 出版日期2010-9