Avtor/Urednik		Szilágyi, Bence; Kovács, Péter; Ferenczy, György G.; Rácz, Anita; Németh, Kristina; Visy, Julia; Szabó, Pál; Ilaš, Janez; Balogh, György T.; Monostory, Katalin; Vincze, István; Tábi, Tamás; Szökő, Éva; Keserü M., György
Naslov		Discovery of isatin and 1H-indazol-3-ol derivatives as D-amino acid oxidase (DAAO) inhibitors
Tip		članek
Vol. in št.		Letnik 26, št. 8
Leto izdaje		2018
Obseg		str. 1579-1587
ISSN		0968-0896 - Bioorganic & Medicinal Chemistry
Jezik		eng
Abstrakt		d-Amino acid oxidase (DAAO) is a potential target in the treatment of schizophrenia as its inhibition increases brain d-serine level and thus contributes to NMDA receptor activation. Inhibitors of DAAO were sought testing [6+5] type heterocycles and identified isatin derivatives as micromolar DAAO inhibitors. A pharmacophore and structure-activity relationship analysis of isatins and reported DAAO inhibitors led us to investigate 1H-indazol-3-ol derivatives and nanomolar inhibitors were identified. The series was further characterized by pKa and isothermal titration calorimetry measurements. Representative compounds exhibited beneficial properties in in vitro metabolic stability and PAMPA assays. 6-fluoro-1H-indazol-3-ol (37) significantly increased plasma d-serine level in an in vivo study on mice. These results show that the 1H-indazol-3-ol series represents a novel class of DAAO inhibitors with the potential to develop drug candidates.
Deskriptorji		Shizofrenija
Proste vsebinske oznake		D-Amino acid oxidase optimization protonation state binding thermodynamics