Identification of an Orally Bioavailable, Potent, and Selective Inhibitor of GlyT1

Wesley P Blackaby; Richard T Lewis; Joanne L Thomson; Andrew S R Jennings; Simon C Goodacre; Leslie J Street; Angus M MacLeod; Andrew Pike; Suzanne Wood; Steve Thomas; Terry A Brown; Alison Smith; Gopalan Pillai; Sarah Almond; Martin R Guscott; H Donald Burns; Waisi Eng; Christine Ryan; Jacquelynn Cook; Terence G Hamill

doi:10.1021/ml1001085

Identification of an Orally Bioavailable, Potent, and Selective Inhibitor of GlyT1

ACS Med Chem Lett. 2010 Jun 25;1(7):350-4. doi: 10.1021/ml1001085. eCollection 2010 Oct 14.

Authors

Wesley P Blackaby¹, Richard T Lewis¹, Joanne L Thomson¹, Andrew S R Jennings¹, Simon C Goodacre¹, Leslie J Street¹, Angus M MacLeod¹, Andrew Pike¹, Suzanne Wood¹, Steve Thomas¹, Terry A Brown¹, Alison Smith¹, Gopalan Pillai¹, Sarah Almond¹, Martin R Guscott¹, H Donald Burns², Waisi Eng², Christine Ryan², Jacquelynn Cook², Terence G Hamill²

Affiliations

¹ Merck Sharp and Dohme, Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, United Kingdom.
² Research Imaging, Merck Research Laboratories, West Point, Pennsylvania 19486.

Abstract

Amalgamation of the structure-activity relationship of two series of GlyT1 inhibitors developed at Merck led to the discovery of a clinical candidate, compound 16 (DCCCyB), which demonstrated excellent in vivo occupancy of GlyT1 transporters in rhesus monkey as determined by displacement of a PET tracer ligand.

Keywords: DCCCyB; GlyT1; Inhibitor; PET tracer ligand; structure−activity relationship.