PMID- 28778464
OWN - NLM
STAT- MEDLINE
DCOM- 20180723
LR  - 20181115
IS  - 1879-0720 (Electronic)
IS  - 0928-0987 (Print)
IS  - 0928-0987 (Linking)
VI  - 109
DP  - 2017 Nov 15
TI  - A Phase I randomized clinical trial testing the safety, tolerability and 
      preliminary pharmacokinetics of the mGluR5 negative allosteric modulator GET 73 
      following single and repeated doses in healthy volunteers.
PG  - 78-85
LID - S0928-0987(17)30430-X [pii]
LID - 10.1016/j.ejps.2017.07.031 [doi]
AB  - Preclinical work suggests that the metabotropic glutamate receptor subtype 5 
      (mGlu5) may represent a novel target to treat neuropsychiatric disorders, 
      including alcohol use disorder and obesity. The goal of this first-in-man study 
      was to evaluate the safety, tolerability and pharmacokinetics (PK) of GET 73 
      (PubChem SID: 329974174), a novel mGluR5 negative allosteric modulator. This was 
      a double-blind, placebo-controlled, ascending dose, Phase I study conducted in 
      healthy male volunteers in two experiments. GET 73 was administered as single 
      ascending doses (N=48; Experiment 1; 10, 30, 100, 300, 450, 600-mg) or multiple 
      ascending doses (N=32; Experiment 2; 100, 300, 450, 450-mg twice a day). Primary 
      endpoints were the incidence of adverse events (AEs) among drug conditions and 
      drug tolerability. The secondary endpoints were the PK parameters of GET 73 and 
      its metabolite MET 2. Single GET 73 doses of up to 600-mg and repeated ascending 
      doses of up to 450-mg twice/day were safe and well-tolerated. There were no 
      serious or severe AEs. All AEs were mild or moderate in severity. Total GET 73 
      exposure increased with each increased GET 73 dose. A dose-related increase in 
      mean maximum plasma drug concentration was observed after repeated dosing. 
      Maximum plasma drug concentrations occurred between 0.5 and 2.05h after 
      administration in all groups for both single and repeated doses. This 
      first-in-human study indicates that GET 73, as single or multiple ascending 
      doses, is safe and well-tolerated when administered to healthy male volunteers.
CI  - Copyright (c) 2017 Elsevier B.V. All rights reserved.
FAU - Haass-Koffler, Carolina L
AU  - Haass-Koffler CL
AD  - Center for Alcohol and Addiction Studies, Department of Psychiatry and Human 
      Behavior, Brown University, Providence, RI, USA; Center for Alcohol and Addiction 
      Studies, Department of Behavioral and Social Sciences, Brown University, 
      Providence, RI, USA. Electronic address: carolina_haass-koffler@brown.edu.
FAU - Goodyear, Kimberly
AU  - Goodyear K
AD  - Center for Alcohol and Addiction Studies, Department of Behavioral and Social 
      Sciences, Brown University, Providence, RI, USA.
FAU - Long, Victoria M
AU  - Long VM
AD  - Center for Alcohol and Addiction Studies, Department of Behavioral and Social 
      Sciences, Brown University, Providence, RI, USA.
FAU - Tran, Harrison H
AU  - Tran HH
AD  - Center for Alcohol and Addiction Studies, Department of Behavioral and Social 
      Sciences, Brown University, Providence, RI, USA.
FAU - Loche, Antonella
AU  - Loche A
AD  - Laboratorio CT, San Remo, Italy.
FAU - Cacciaglia, Roberto
AU  - Cacciaglia R
AD  - Laboratorio CT, San Remo, Italy.
FAU - Swift, Robert M
AU  - Swift RM
AD  - Center for Alcohol and Addiction Studies, Department of Psychiatry and Human 
      Behavior, Brown University, Providence, RI, USA.
FAU - Leggio, Lorenzo
AU  - Leggio L
AD  - Center for Alcohol and Addiction Studies, Department of Behavioral and Social 
      Sciences, Brown University, Providence, RI, USA.
LA  - eng
GR  - K01 AA023867/AA/NIAAA NIH HHS/United States
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Randomized Controlled Trial
DEP - 20170801
PL  - Netherlands
TA  - Eur J Pharm Sci
JT  - European journal of pharmaceutical sciences : official journal of the European 
      Federation for Pharmaceutical Sciences
JID - 9317982
RN  - 0 (Anilides)
RN  - 0 (Anti-Obesity Agents)
RN  - 0 (GRM5 protein, human)
RN  - 0 (N-(4-trifluoromethylbenzyl)-4-methoxybutanamide)
RN  - 0 (Receptor, Metabotropic Glutamate 5)
SB  - IM
MH  - Adult
MH  - Anilides/*administration & dosage/adverse effects/pharmacokinetics
MH  - Anti-Obesity Agents/*administration & dosage/adverse effects/pharmacokinetics
MH  - Double-Blind Method
MH  - Electrocardiography
MH  - Healthy Volunteers
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Receptor, Metabotropic Glutamate 5/metabolism
MH  - Young Adult
PMC - PMC5776031
MID - NIHMS932074
OTO - NOTNLM
OT  - Allosteric modulator
OT  - GET 73
OT  - Glutamate receptor subtype 5 (mGlu5)
OT  - Safety
OT  - Tolerability
COIS- The other authors report no biomedical financial interests or potential conflicts 
      of interest.
EDAT- 2017/08/06 06:00
MHDA- 2018/07/24 06:00
PMCR- 2018/11/15
CRDT- 2017/08/06 06:00
PHST- 2017/03/30 00:00 [received]
PHST- 2017/07/27 00:00 [revised]
PHST- 2017/07/28 00:00 [accepted]
PHST- 2017/08/06 06:00 [pubmed]
PHST- 2018/07/24 06:00 [medline]
PHST- 2017/08/06 06:00 [entrez]
PHST- 2018/11/15 00:00 [pmc-release]
AID - S0928-0987(17)30430-X [pii]
AID - 10.1016/j.ejps.2017.07.031 [doi]
PST - ppublish
SO  - Eur J Pharm Sci. 2017 Nov 15;109:78-85. doi: 10.1016/j.ejps.2017.07.031. Epub 
      2017 Aug 1.