Triazoloquinazolines as a novel class of phosphodiesterase 10A (PDE10A) inhibitors

Jan Kehler; Andreas Ritzen; Morten Langgård; Sebastian Leth Petersen; Mohamed M Farah; Christoffer Bundgaard; Claus Tornby Christoffersen; Jacob Nielsen; John Paul Kilburn

doi:10.1016/j.bmcl.2011.04.067

Triazoloquinazolines as a novel class of phosphodiesterase 10A (PDE10A) inhibitors

Bioorg Med Chem Lett. 2011 Jun 15;21(12):3738-42. doi: 10.1016/j.bmcl.2011.04.067. Epub 2011 Apr 30.

Authors

Jan Kehler¹, Andreas Ritzen, Morten Langgård, Sebastian Leth Petersen, Mohamed M Farah, Christoffer Bundgaard, Claus Tornby Christoffersen, Jacob Nielsen, John Paul Kilburn

Affiliation

¹ H. Lundbeck A/S, Department of Discovery Chemistry & DMPK, Valby, Denmark. jke@lundbeck.com

PMID: 21602043
DOI: 10.1016/j.bmcl.2011.04.067

Abstract

Novel triazoloquinazolines have been found as phosphodiesterase 10A (PDE10A) inhibitors. Structure-activity studies improved the initial micromolar potency which was found in the lead compound by a 100-fold identifying 5-(1H-benzoimidazol-2-ylmethylsulfanyl)-2-methyl-[1,2,4]triazolo[1,5-c]quinazoline, 42 (PDE10A IC(50)=12 nM) as the most potent compound from the series. Two X-ray structures revealed novel binding modes to the catalytic site of the PDE10A enzyme.

MeSH terms

Animals
Benzimidazoles / chemical synthesis*
Benzimidazoles / chemistry
Benzimidazoles / pharmacology*
Crystallography, X-Ray
Enzyme Activation / drug effects
Inhibitory Concentration 50
Models, Molecular
Molecular Structure
Phosphodiesterase Inhibitors / chemical synthesis*
Phosphodiesterase Inhibitors / chemistry
Phosphodiesterase Inhibitors / pharmacology
Phosphoric Diester Hydrolases / metabolism*
Protein Binding
Quinazolines / chemical synthesis*
Quinazolines / chemistry
Quinazolines / pharmacology*
Rats

Substances

5-(1H-benzoimidazol-2-ylmethylsulfanyl)-2-methyl(1,2,4)triazolo(1,5-c)quinazoline
Benzimidazoles
Phosphodiesterase Inhibitors
Quinazolines
PDE10A protein, human
Phosphoric Diester Hydrolases