Synthesis and pharmacological evaluation of new pyrazolidine-3, 5-diones as AT(1) angiotensin II receptor antagonists.
On the basis of the structure of the non-peptide receptor antagonist irbesartan, a new series of AT(1) ligands was designed. In these compounds the central imidazolone nucleus of irbesartan was replaced by a pyrazolidine-3,5-dione structure. The key intermediate N-alkylpyrazolidine-3,5-diones were synthesized according to a new and general method. The most active compounds possess a spirocyclopentane ring at position 4, a linear butyl chain at position 1, and the [2'-(5-tetrazolyl)biphenyl-4-yl]methyl or [2'-(benzoylaminosulfonyl)biphenyl-4-yl]methyl group at position 2. Affinity toward the AT(1) and AT(2) receptors was assessed by the ability of the compounds to competitively displace [(3)H]AII from its specific binding sites. The most active compounds, 28 and 48, displayed high affinity for the AT(1) receptor, good selectivity AT(1) versus AT(2), and potent in vitro antagonist activity.
Le Bourdonnec
B
B
Institut de Chimie Pharmaceutique Albert Lespagnol and Laboratoire de Chimie Analytique, Faculté des Sciences Pharmaceutiques et Biologiques, Université de Lille 2, rue du Professeur Laguesse, BP 83, F-59006 Lille, France. lebou001@tc.umn.edu
Meulon
E
E
Yous
S
S
Goossens
J F
JF
Houssin
R
R
Hénichart
J P
JP
D000804:Angiotensin II / Q000378:metabolism*; D057911:Angiotensin Receptor Antagonists; D001667:Binding, Competitive; D001713:Biphenyl Compounds / Q000737:chemistry; D002118:Calcium / Q000378:metabolism; D006801:Humans; D000077405:Irbesartan; D008024:Ligands; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000378:metabolism; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000737:chemistry; D014407:Tumor Cells, Cultured
C411458:2-butyl-3-((2'-(1H-tetrazol-5-yl)(1,1'-biphenyl)-4-yl)methyl)-2,3-diazaspiro(4.4)nonane-1,4-dione; C411459:3-((2'-(benzoylaminosulfonyl)(1,1'-biphenyl)-4-yl)methyl)-2-butyl-2,3-diazaspiro(4.4)nonane-1,4-dione; D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D008024:Ligands; D011720:Pyrazoles; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D013141:Spiro Compounds; D013777:Tetrazoles; D000804:Angiotensin II; D000077405:Irbesartan; D002118:Calcium