title: Design, synthesis, and biological evaluation of AT1 angiotensin II receptor antagonists based on the pyrazolo[3,4-b]pyridine and related heteroaromatic bicyclic systems.
abstract: Novel AT 1 receptor antagonists bearing the pyrazolo[3,4- b]pyridine bicyclic heteroaromatic system (or structurally related moieties) were designed and synthesized as the final step of a large program devoted to the development of new antihypertensive agents and to the understanding of the molecular basis of their pharmacodynamic and pharmacokinetic properties. The preliminary pharmacological characterization revealed nanomolar AT 1 receptor affinity for several compounds of the series and a potent antagonistic activity in isolated rabbit aortic strip functional assay for 7c and 8a. These results stimulated the study of the biopharmaceutical properties of some selected compounds, which were found to be characterized by a permeability from medium to high. Remarkably, the least permeable 7c showed both permeability and oral bioavailability (80%) higher than losartan, but its terminal half-life was shorter. These results suggest that the permeability is not a limiting factor in the pharmacokinetics of these AT 1 receptor antagonists.
authors.affiliation: Dipartimento Farmaco Chimico Tecnologico and European Research Centre for Drug Discovery and Development, Università di Siena, Via A. Moro, Siena, Italy. cappelli@unisi.it
authors.forename: Andrea
authors.initials: A
authors.lastname: Cappelli
authors.forename: Chiara
authors.initials: C
authors.lastname: Nannicini
authors.forename: Andrea
authors.initials: A
authors.lastname: Gallelli
authors.forename: Germano
authors.initials: G
authors.lastname: Giuliani
authors.forename: Salvatore
authors.initials: S
authors.lastname: Valenti
authors.forename: Gal la Pericot
authors.initials: Gl
authors.lastname: Mohr
authors.forename: Maurizio
authors.initials: M
authors.lastname: Anzini
authors.forename: Laura
authors.initials: L
authors.lastname: Mennuni
authors.forename: Flora
authors.initials: F
authors.lastname: Ferrari
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Caselli
authors.forename: Antonio
authors.initials: A
authors.lastname: Giordani
authors.forename: Walter
authors.initials: W
authors.lastname: Peris
authors.forename: Francesco
authors.initials: F
authors.lastname: Makovec
authors.forename: Gianluca
authors.initials: G
authors.lastname: Giorgi
authors.forename: Salvatore
authors.initials: S
authors.lastname: Vomero
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability / Q000187:drug effects; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D007413:Intestinal Mucosa / Q000187:drug effects; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D019086:Bridged Bicyclo Compounds, Heterocyclic; D011720:Pyrazoles; D011725:Pyridines; D044140:Receptor, Angiotensin, Type 1; C447480:pyrazolo(3,4-b)pyridine