Novel GlyT1 inhibitor chemotypes by scaffold hopping. Part 2: development of a [3.3.0]-based series and other piperidine bioisosteres.
This Letter describes the development and SAR of a novel series of GlyT1 inhibitors derived from a scaffold hopping approach, in lieu of an HTS campaign, which provided intellectual property position. Members within this new [3.3.0]-based series displayed excellent GlyT1 potency, selectivity, free fraction, and modest CNS penetration. Moreover, enantioselective GlyT1 inhibition was observed, within this novel series and a number of other piperidine bioisosteric cores.
Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Apoptosis and Cell Death Research Program and Conrad Prebys Center for Chemical Genomics, Sanford-Burnham Medical Research Institute, 10901 N. Torrey Pines Rd., La Jolla, CA 92037, USA.
Douglas J
DJ
Sheffler
Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Michael T
MT
Nedelcovych
Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Centre for Cancer Research and Cell Biology, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK.
Richard
R
Williams
Department of Pharmaceutical Sciences, Lipscomb University, College of Pharmacy and Health Sciences, Nashville, TN 37024-3951, USA.
Stephen C
SC
Turner
Department of Pharmaceutical Sciences, Lipscomb University, College of Pharmacy and Health Sciences, Nashville, TN 37024-3951, USA.
Brittany B
BB
Duerk
Department of Pharmaceutical Sciences, Lipscomb University, College of Pharmacy and Health Sciences, Nashville, TN 37024-3951, USA.
Megan R
MR
Robbins
Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Sataya B
SB
Jadhav
Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Specialized Chemistry Center for Probe Development (MLPCN), Nashville, TN 37232, USA.
Colleen M
CM
Niswender
Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Carrie K
CK
Jones
Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Specialized Chemistry Center for Probe Development (MLPCN), Nashville, TN 37232, USA.
P Jeffrey
PJ
Conn
Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmaceutical Sciences, Lipscomb University, College of Pharmacy and Health Sciences, Nashville, TN 37024-3951, USA. Electronic address: nate.daniels@lipscomb.edu.
R Nathan
RN
Daniels
Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Specialized Chemistry Center for Probe Development (MLPCN), Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA. Electronic address: craig.lindsley@vanderbilt.edu.
Craig W
CW
Lindsley
D004305:Dose-Response Relationship, Drug; D050487:Glycine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D015394:Molecular Structure; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
D050487:Glycine Plasma Membrane Transport Proteins; D010880:Piperidines; C493268:SLC6A9 protein, human; D013449:Sulfonamides; C032727:piperidine
GlyT1; Scaffold hopping; Schizophrenia; Transporter