Pharmacophore, drug metabolism, and pharmacokinetics models on non-peptide AT1, AT2, and AT1/AT2 angiotensin II receptor antagonists.
About 20 non-peptide angiotensin II receptor antagonists are in various stages of clinical development. Different modeling approaches were used to predict the pharmacophoric requirements for AT(1) (angiotensin II receptor subtype 1) affinity. However, to our knowledge, none was used to predict both the selectivity toward AT(1) and AT(2) (angiotensin II receptor subtype 2) receptor subtypes. In this paper, partial least squares discriminant analysis is applied to derive the chemical features guiding AT(1) and AT(2) selectivity or mixed AT(1)/AT(2) receptor binding. The method can be used to modulate AT(1) versus AT(2) selectivity. Concerns that unopposed stimulation of the AT(2) receptor might produce adverse effects initiated a search for new balanced antagonists. Moreover, it can serve as a fast filtering procedure in database searches. Finally, some relevant pharmacokinetics and metabolic properties of the database of 53 compounds are calculated using the VolSurf and MetaSite software to allow the simultaneous characterization of pharmacodynamic and pharmacokinetics properties of the chemical space of angiotensin II receptor antagonists.
Laboratory for Chemometrics and Cheminformatics, Department of Chemistry, University of Perugia, Via Elce di sotto 10, I-06123 Perugia, Italy.
Giuliano
G
Berellini
Gabriele
G
Cruciani
Raimund
R
Mannhold
D047228:Angiotensin II Type 1 Receptor Blockers / Q000737:chemistry* / Q000494:pharmacology*; D001562:Benzimidazoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D001665:Binding Sites; D001713:Biphenyl Compounds; D007700:Kinetics; D019808:Losartan / Q000493:pharmacokinetics / Q000494:pharmacology*; D008958:Models, Molecular; D008968:Molecular Conformation; D010084:Oxidation-Reduction; D004364:Pharmaceutical Preparations / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects / Q000378:metabolism*; D044139:Receptor, Angiotensin, Type 2 / Q000187:drug effects / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000493:pharmacokinetics / Q000494:pharmacology*
D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D004364:Pharmaceutical Preparations; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D013777:Tetrazoles; D019808:Losartan; C081643:candesartan