Novel triazines as potent and selective phosphodiesterase 10A inhibitors

Michael S. Malamas, Hans Stange, Rudolf Schindler, Hans Joachim Lankau, Christian Grunwald, Barbara Langen, Ute Egerland, Thorsten Hage, Yike Ni, James Erdei, Kristi Yi Fan, Kevin Parris, Karen L. Marquis, Steve Grauer, Julie Brennan, Rachel Navarra, Radka Graf, Boyd L. Harrison, Albert Robichaud, Thomas KronbachMenelas N. Pangalos, Nicholas J. Brandon, Norbert Hoefgen

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

The identification of highly potent and orally active triazines for the inhibition of PDE10A is reported. The new analogs exhibit low-nanomolar potency for PDE10A, demonstrate high selectivity against all other members of the PDE family, and show desired drug-like properties. Employing structure-based drug design approaches, we investigated the selectivity of PDE10A inhibitors against other known PDE isoforms, by methodically exploring the various sub-regions of the PDE10A ligand binding pocket. A systematic assessment of the ADME and pharmacokinetic properties of the newly synthesized compounds has led to the design of drug-like candidates with good brain permeability and desirable drug kinetics (t1/2, bioavailability, clearance). Compound 66 was highly potent for PDE10A (IC50 = 1.4 nM), demonstrated high selectivity (>200×) for the other PDEs, and was efficacious in animal models of psychoses; reversal of MK-801 induced hyperactivity (MED = 0.1 mg/kg) and conditioned avoidance responding (CAR; ID50 = 0.2 mg/kg).

Original languageEnglish (US)
Pages (from-to)5876-5884
Number of pages9
JournalBioorganic and Medicinal Chemistry Letters
Volume22
Issue number18
DOIs
StatePublished - Sep 15 2012
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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