Evolution and synthesis of novel orally bioavailable inhibitors of PDE10A. Issue 9 (1st May 2015)

• Record 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.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 25:Issue 9(2015)
• Page Start: 1864
• Page End: 1868
• Publication Date: 2015-05-01
• Subjects: PDE10A -- PDE10A inhibitor -- Phosphodiesterase inhibitor -- PCP-induced hyperlocomotion -- Schizophrenia; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2015.03.050
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: The evolution and synthesis of potent, orally bioavailable inhibitors of PDE10A is described. Abstract: 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. Compound39 was highly potent versus PDE10A (IC50 = 1.0 nM), demonstrated high selectivity (>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.