Dihydrothiazolopyridone derivatives as a novel family of positive allosteric modulators of the metabotropic glutamate 5 (mGlu5) receptor.
Starting from a singleton chromanone high throughput screening (HTS) hit, we describe a focused medicinal chemistry optimization effort leading to the identification of a novel series of phenoxymethyl-dihydrothiazolopyridone derivatives as selective positive allosteric modulators (PAMs) of the metabotropic glutamate 5 (mGlu5) receptor. These dihydrothiazolopyridones potentiate receptor responses in recombinant systems. In vitro and in vivo drug metabolism and pharmacokinetic (DMPK) evaluation allowed us to select compound 16a for its assessment in a preclinical animal screen of possible antipsychotic activity. 16a was able to reverse amphetamine-induced hyperlocomotion in rats in a dose-dependent manner without showing any significant motor impairment or overt neurological side effects at comparable doses. Evolution of our medicinal chemistry program, structure activity, and properties relationships (SAR and SPR) analysis as well as a detailed profile for optimized mGlu5 receptor PAM 16a are described.
Neuroscience Medicinal Chemistry, ¶CREATe Analytical Sciences, and ‡CREATe Molecular Informatics, Janssen Research and Development , Jarama 75, 45007 Toledo, Spain.
José Manuel
JM
Bartolomé-Nebreda
Susana
S
Conde-Ceide
Francisca
F
Delgado
Laura
L
Iturrino
Joaquín
J
Pastor
Miguel Ángel
MÁ
Pena
Andrés A
AA
Trabanco
Gary
G
Tresadern
Carola M
CM
Wassvik
Shaun R
SR
Stauffer
Satyawan
S
Jadhav
Kiran
K
Gogi
Paige N
PN
Vinson
Meredith J
MJ
Noetzel
Emily
E
Days
C David
CD
Weaver
Craig W
CW
Lindsley
Colleen M
CM
Niswender
Carrie K
CK
Jones
P Jeffrey
PJ
Conn
Frederik
F
Rombouts
Hilde
H
Lavreysen
Gregor J
GJ
Macdonald
Claire
C
Mackie
Thomas
T
Steckler
D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D014150:Antipsychotic Agents / Q000737:chemistry* / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008124:Locomotion / Q000187:drug effects; D008297:Male; D051381:Rats; D064529:Receptor, Metabotropic Glutamate 5 / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry* / Q000494:pharmacology*
D014150:Antipsychotic Agents; D064529:Receptor, Metabotropic Glutamate 5; D013844:Thiazoles