title: Synthesis and Biological Evaluation of N-((1-(4-(Sulfonyl)piperazin-1-yl)cycloalkyl)methyl)benzamide Inhibitors of Glycine Transporter-1.
abstract: We previously disclosed the discovery of rationally designed N-((1-(4-(propylsulfonyl)piperazin-1-yl)cycloalkyl)methyl)benzamide inhibitors of glycine transporter-1 (GlyT-1), represented by analogues 10 and 11. We describe herein further structure-activity relationship exploration of this series via an optimization strategy that primarily focused on the sulfonamide and benzamide appendages of the scaffold. These efforts led to the identification of advanced leads possessing a desirable balance of excellent in vitro GlyT-1 potency and selectivity, favorable ADME and in vitro pharmacological profiles, and suitable pharmacokinetic and safety characteristics. Representative analogue (+)-67 exhibited robust in vivo activity in the cerebral spinal fluid glycine biomarker model in both rodents and nonhuman primates. Furthermore, rodent microdialysis experiments also demonstrated that oral administration of (+)-67 significantly elevated extracellular glycine levels within the medial prefrontal cortex (mPFC).
authors: Department of Medicinal Chemistry, AMRI , East Campus, 3 University Place, Rensselaer, New York 12144, United States.
authors: Christopher L
authors: CL
authors: Cioffi
authors: Department of Medicinal Chemistry, AMRI , East Campus, 3 University Place, Rensselaer, New York 12144, United States.
authors: Shuang
authors: S
authors: Liu
authors: Department of Medicinal Chemistry, AMRI , East Campus, 3 University Place, Rensselaer, New York 12144, United States.
authors: Mark A
authors: MA
authors: Wolf
authors: Department of Medicinal Chemistry, AMRI , East Campus, 3 University Place, Rensselaer, New York 12144, United States.
authors: Peter R
authors: PR
authors: Guzzo
authors: Discovery Research and Development Chemistry, Singapore Research Center, AMRI , 61 Science Park Road, Science Park III, 117525, Singapore.
authors: Kashinath
authors: K
authors: Sadalapure
authors: Discovery Research and Development Chemistry, Singapore Research Center, AMRI , 61 Science Park Road, Science Park III, 117525, Singapore.
authors: Visweswaran
authors: V
authors: Parthasarathy
authors: Discovery Research and Development Chemistry, Singapore Research Center, AMRI , 61 Science Park Road, Science Park III, 117525, Singapore.
authors: David T J
authors: DT
authors: Loong
authors: Discovery Research and Development Chemistry, Singapore Research Center, AMRI , 61 Science Park Road, Science Park III, 117525, Singapore.
authors: Jun-Ho
authors: JH
authors: Maeng
authors: Discovery Research and Development Chemistry, Singapore Research Center, AMRI , 61 Science Park Road, Science Park III, 117525, Singapore.
authors: Edmund
authors: E
authors: Carulli
authors: Discovery Research and Development Chemistry, Singapore Research Center, AMRI , 61 Science Park Road, Science Park III, 117525, Singapore.
authors: Xiao
authors: X
authors: Fang
authors: Discovery Research and Development Chemistry, Singapore Research Center, AMRI , 61 Science Park Road, Science Park III, 117525, Singapore.
authors: Kalesh
authors: K
authors: Karunakaran
authors: Discovery Research and Development Chemistry, Singapore Research Center, AMRI , 61 Science Park Road, Science Park III, 117525, Singapore.
authors: Lakshman
authors: L
authors: Matta
authors: Discovery Research and Development Chemistry, Singapore Research Center, AMRI , 61 Science Park Road, Science Park III, 117525, Singapore.
authors: Sok Hui
authors: SH
authors: Choo
authors: Discovery Research and Development Chemistry, Singapore Research Center, AMRI , 61 Science Park Road, Science Park III, 117525, Singapore.
authors: Shailijia
authors: S
authors: Panduga
authors: Department of Medicinal Chemistry, AMRI , East Campus, 3 University Place, Rensselaer, New York 12144, United States.
authors: Ronald N
authors: RN
authors: Buckle
authors: Department of Medicinal Chemistry, AMRI , East Campus, 3 University Place, Rensselaer, New York 12144, United States.
authors: Randall N
authors: RN
authors: Davis
authors: Department of Medicinal Chemistry, AMRI , East Campus, 3 University Place, Rensselaer, New York 12144, United States.
authors: Samuel A
authors: SA
authors: Sakwa
authors: Discovery Research and Development Chemistry, Singapore Research Center, AMRI , 61 Science Park Road, Science Park III, 117525, Singapore.
authors: Priya
authors: P
authors: Gupta
authors: Department of Medicinal Chemistry, AMRI , East Campus, 3 University Place, Rensselaer, New York 12144, United States.
authors: Bruce J
authors: BJ
authors: Sargent
authors: Department of Medicinal Chemistry, AMRI , East Campus, 3 University Place, Rensselaer, New York 12144, United States.
authors: Nicholas A
authors: NA
authors: Moore
authors: Bothell Research Center, AMRI , 22215 26th Ave SE, Bothell, Washington 98021-4425, United States.
authors: Michele M
authors: MM
authors: Luche
authors: Bothell Research Center, AMRI , 22215 26th Ave SE, Bothell, Washington 98021-4425, United States.
authors: Grant J
authors: GJ
authors: Carr
authors: Drug Metabolism and Pharmacokinetics, AMRI , East Campus, 17 University Place, Rensselaer, New York 12144, United States.
authors: Yuri L
authors: YL
authors: Khmelnitsky
authors: Drug Metabolism and Pharmacokinetics, AMRI , East Campus, 17 University Place, Rensselaer, New York 12144, United States.
authors: Jiffry
authors: J
authors: Ismail
authors: Discovery Research and Development Chemistry, Singapore Research Center, AMRI , 61 Science Park Road, Science Park III, 117525, Singapore.
authors: Mark
authors: M
authors: Chung
authors: Discovery Research and Development Chemistry, Singapore Research Center, AMRI , 61 Science Park Road, Science Park III, 117525, Singapore.
authors: Mei
authors: M
authors: Bai
authors: Discovery Research and Development Chemistry, Singapore Research Center, AMRI , 61 Science Park Road, Science Park III, 117525, Singapore.
authors: Wei Yee
authors: WY
authors: Leong
authors: Discovery Research and Development Chemistry, Singapore Research Center, AMRI , 61 Science Park Road, Science Park III, 117525, Singapore.
authors: Nidhi
authors: N
authors: Sachdev
authors: Discovery Research and Development Chemistry, Singapore Research Center, AMRI , 61 Science Park Road, Science Park III, 117525, Singapore.
authors: Srividya
authors: S
authors: Swaminathan
authors: Bothell Research Center, AMRI , 22215 26th Ave SE, Bothell, Washington 98021-4425, United States.
authors: Andrew J
authors: AJ
authors: Mhyre
mesh_terms: D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D005998:Glycine / Q000134:cerebrospinal fluid / Q000378:metabolism; D050487:Glycine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008252:Macaca fascicularis; D008297:Male; D008745:Methylation; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: D001549:Benzamides; D050487:Glycine Plasma Membrane Transport Proteins; D010879:Piperazines; D005998:Glycine