Evolution and synthesis of novel orally bioavailable inhibitors of PDE10A.

Publication Type:

Journal Article

Authors:

Burdi, Douglas F; Campbell, John E; Wang, Jun; Zhao, Sufang; Zhong, Hua; Wei, Jianfeng; Campbell, Una; Shao, Liming; Herman, Lee; Koch, Patrick; Jones, Philip G; Hewitt, Michael C

Source:

Bioorg Med Chem Lett, Volume 25, Issue 9, p.1864-8 (2015)

Keywords:

Administration, Oral, Animals, Biological Availability, Disease Models, Animal, Dose-Response Relationship, Drug, Drug Design, Humans, Locomotion, Models, Molecular, Molecular Structure, Phencyclidine, Phosphoric Diester Hydrolases, Rats, Structure-Activity Relationship, Triazoles

Abstract:

<p>The design and synthesis of highly potent, selective orally bioavailable inhibitors of PDE10A is reported. Starting with an active compound of modest potency from a small focused screen, we were able to evolve this series to a lead molecule with high potency and selectivity versus other PDEs using structure-based design. A systematic refinement of ADME properties during lead optimization led to a lead compound with good half-life that was brain penetrant. Compound 39 was highly potent versus PDE10A (IC50=1.0 nM), demonstrated high selectivity (&gt;1000-fold) against other PDEs and was efficacious when dosed orally in a rat model of psychosis, PCP-induced hyperlocomotion with an EC50 of 1 mg/kg.</p>

PDB: 
4YQH, 4YS7
Detector: 
PILATUS
Beamline: 
24-ID-C