title: Discovery of 7-N-piperazinylthiazolo[5,4-d]pyrimidine analogues as a novel class of immunosuppressive agents with in vivo biological activity.
abstract: Herein we describe the synthesis and in vitro and in vivo activity of thiazolo[5,4-d]pyrimidines as a novel class of immunosuppressive agents, useful for preventing graft rejection after organ transplantation. This research resulted in the discovery of a series of compounds with potent activity in the mixed lymphocyte reaction (MLR) assay, which is well-known as the in vitro model for in vivo rejection after organ transplantation. The most potent congeners displayed IC(50) values of less than 50 nM in this MLR assay and hence are equipotent to cyclosporin A, a clinically used immunosuppressive drug. One representative of this series was further evaluated in a preclinical animal model of organ transplantation and showed excellent in vivo efficacy. It validates these compounds as new promising immunosuppressive drugs.
authors.affiliation: Laboratory of Medicinal Chemistry, Rega Institute for Medical Research, Katholieke Universiteit Leuven, Minderbroedersstraat 10, 3000 Leuven, Belgium.
authors.forename: Mi-Yeon
authors.initials: MY
authors.lastname: Jang
authors.forename: Yuan
authors.initials: Y
authors.lastname: Lin
authors.forename: Steven
authors.initials: S
authors.lastname: De Jonghe
authors.forename: Ling-Jie
authors.initials: LJ
authors.lastname: Gao
authors.forename: Bart
authors.initials: B
authors.lastname: Vanderhoydonck
authors.forename: Mathy
authors.initials: M
authors.lastname: Froeyen
authors.forename: Jef
authors.initials: J
authors.lastname: Rozenski
authors.forename: Jean
authors.initials: J
authors.lastname: Herman
authors.forename: Thierry
authors.initials: T
authors.lastname: Louat
authors.forename: Kristien
authors.initials: K
authors.lastname: Van Belle
authors.forename: Mark
authors.initials: M
authors.lastname: Waer
authors.forename: Piet
authors.initials: P
authors.lastname: Herdewijn
mesh_terms: D000818:Animals; D005260:Female; D006084:Graft Rejection / Q000517:prevention & control; D006085:Graft Survival / Q000187:drug effects; D016027:Heart Transplantation; D006801:Humans; D007166:Immunosuppressive Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D015394:Molecular Structure; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014184:Transplantation, Homologous
chemical_list: D007166:Immunosuppressive Agents; D010879:Piperazines; D011743:Pyrimidines; D013844:Thiazoles