TY - JOUR
T1 - 4-Aryl-3-arylsulfonyl-quinolines as negative allosteric modulators of metabotropic GluR5 receptors
T2 - From HTS hit to development candidate
AU - Galambos, János
AU - Domány, György
AU - Nógrádi, Katalin
AU - Wágner, Gábor
AU - Keseru, György M.
AU - Bobok, Amrita
AU - Kolok, Sándor
AU - Mikó-Bakk, Mónika L.
AU - Vastag, Mónika
AU - Sághy, Katalin
AU - Kóti, János
AU - Szakács, Zoltán
AU - Béni, Zoltán
AU - Gál, Krisztina
AU - Szombathelyi, Zsolt
AU - Greiner, István
PY - 2016/2/15
Y1 - 2016/2/15
N2 - High throughput screening of our corporate compound library followed by hit-to-lead development resulted in a 4-aryl-3-arylsulfonyl-quinoline derivative lead (2) with mGluR5 negative allosteric modulator activity. During the lead optimization process, our objective was to improve affinity and metabolic stability. Modifications at the three targeted regions of the lead structure resulted in compounds with nanomolar affinity and acceptable metabolic stability. One of the most promising compounds (3), showing excellent in vivo efficacy, was selected for preclinical development and subsequent phase I clinical studies.
AB - High throughput screening of our corporate compound library followed by hit-to-lead development resulted in a 4-aryl-3-arylsulfonyl-quinoline derivative lead (2) with mGluR5 negative allosteric modulator activity. During the lead optimization process, our objective was to improve affinity and metabolic stability. Modifications at the three targeted regions of the lead structure resulted in compounds with nanomolar affinity and acceptable metabolic stability. One of the most promising compounds (3), showing excellent in vivo efficacy, was selected for preclinical development and subsequent phase I clinical studies.
KW - 4-Aryl-3-arylsulfonyl-quinolines
KW - mGluR5
KW - Negative allosteric modulator
UR - http://www.scopus.com/inward/record.url?scp=84958212557&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84958212557&partnerID=8YFLogxK
U2 - 10.1016/j.bmcl.2016.01.024
DO - 10.1016/j.bmcl.2016.01.024
M3 - Article
C2 - 26774652
AN - SCOPUS:84958212557
SN - 0960-894X
VL - 26
SP - 1249
EP - 1252
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
IS - 4
ER -