PDBsum entry 2o8h

Hydrolase

PDB id: 2o8h

Contents

Protein chain

307 a.a.

Ligands

227

Metals

_ZN

_MG

Waters ×312

References listed in PDB file

Key reference

• Title: Discovery of a series of 6,7-Dimethoxy-4-Pyrrolidylquinazoline pde10a inhibitors.
• Authors: T.A.Chappie, J.M.Humphrey, M.P.Allen, K.G.Estep, C.B.Fox, L.A.Lebel, S.Liras, E.S.Marr, F.S.Menniti, J.Pandit, C.J.Schmidt, M.Tu, R.D.Williams, F.V.Yang.
• Ref.: J Med Chem, 2007, 50, 182-185. [DOI no: 10.1021/jm060653b]
• PubMed id: 17228859

Abstract

A papaverine based pharmacophore model for PDE10A inhibition was generated via SBDD and used to design a library of 4-amino-6,7-dimethoxyquinazolines. From this library emerged an aryl ether pyrrolidyl 6,7-dimethoxyquinazoline series that became the focal point for additional modeling, X-ray, and synthetic efforts toward increasing PDE10A inhibitory potency and selectivity versus PDE3A/B. These efforts culminated in the discovery of 29, a potent and selective brain penetrable inhibitor of PDE10A.