title: 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.
abstract: 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.
authors.affiliation: Department of Chemistry, University of Patras, Patras 26500, Greece. aggelisgeorge@hotmail.com
authors.forename: George
authors.initials: G
authors.lastname: Agelis
authors.forename: Panagiota
authors.initials: P
authors.lastname: Roumelioti
authors.forename: Amalia
authors.initials: A
authors.lastname: Resvani
authors.forename: Serdar
authors.initials: S
authors.lastname: Durdagi
authors.forename: Maria-Eleni
authors.initials: ME
authors.lastname: Androutsou
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Kelaidonis
authors.forename: Demetrios
authors.initials: D
authors.lastname: Vlahakos
authors.forename: Thomas
authors.initials: T
authors.lastname: Mavromoustakos
authors.forename: John
authors.initials: J
authors.lastname: Matsoukas
mesh_terms: D000804:Angiotensin II / Q000037:antagonists & inhibitors*; D057911:Angiotensin Receptor Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis / Q000737:chemistry; D015195:Drug Design; D006801:Humans; D006973:Hypertension / Q000188:drug therapy; D007093:Imidazoles / Q000138:chemical synthesis; D019808:Losartan / Q000031:analogs & derivatives*; D011945:Receptors, Angiotensin / Q000737:chemistry / Q000378:metabolism; D011955:Receptors, Drug / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D007093:Imidazoles; D011945:Receptors, Angiotensin; D011955:Receptors, Drug; D000804:Angiotensin II; D019808:Losartan