Design, synthesis, and biological evaluation of AT1 angiotensin II receptor antagonists based on the pyrazolo[3,4-b]pyridine and related heteroaromatic bicyclic systems

Andrea Cappelli; Chiara Nannicini; Andrea Gallelli; Germano Giuliani; Salvatore Valenti; Gal la Pericot Mohr; Maurizio Anzini; Laura Mennuni; Flora Ferrari; Gianfranco Caselli; Antonio Giordani; Walter Peris; Francesco Makovec; Gianluca Giorgi; Salvatore Vomero

doi:10.1021/jm7011563

Design, synthesis, and biological evaluation of AT1 angiotensin II receptor antagonists based on the pyrazolo[3,4-b]pyridine and related heteroaromatic bicyclic systems

J Med Chem. 2008 Apr 10;51(7):2137-46. doi: 10.1021/jm7011563. Epub 2008 Mar 5.

Authors

Andrea Cappelli¹, Chiara Nannicini, Andrea Gallelli, Germano Giuliani, Salvatore Valenti, Gal la Pericot Mohr, Maurizio Anzini, Laura Mennuni, Flora Ferrari, Gianfranco Caselli, Antonio Giordani, Walter Peris, Francesco Makovec, Gianluca Giorgi, Salvatore Vomero

Affiliation

¹ Dipartimento Farmaco Chimico Tecnologico and European Research Centre for Drug Discovery and Development, Università di Siena, Via A. Moro, Siena, Italy. cappelli@unisi.it

PMID: 18318468
DOI: 10.1021/jm7011563

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Angiotensin II Type 1 Receptor Blockers* / chemical synthesis
Angiotensin II Type 1 Receptor Blockers* / chemistry
Angiotensin II Type 1 Receptor Blockers* / pharmacology
Animals
Aorta, Thoracic / drug effects
Bridged Bicyclo Compounds, Heterocyclic* / chemical synthesis
Bridged Bicyclo Compounds, Heterocyclic* / chemistry
Bridged Bicyclo Compounds, Heterocyclic* / pharmacology
Caco-2 Cells
Cell Membrane Permeability / drug effects
Crystallography, X-Ray
Drug Design
Humans
Intestinal Mucosa / drug effects
Male
Models, Molecular
Molecular Structure
Pyrazoles* / chemical synthesis
Pyrazoles* / chemistry
Pyrazoles* / pharmacology
Pyridines* / chemical synthesis
Pyridines* / chemistry
Pyridines* / pharmacology
Rabbits
Rats
Rats, Wistar
Receptor, Angiotensin, Type 1 / drug effects*
Stereoisomerism
Structure-Activity Relationship

Substances

Angiotensin II Type 1 Receptor Blockers
Bridged Bicyclo Compounds, Heterocyclic
Pyrazoles
Pyridines
Receptor, Angiotensin, Type 1
pyrazolo(3,4-b)pyridine