title: Novel 7H-pyrrolo[2,3-d]pyrimidine derivatives as potent and orally active STAT6 inhibitors.
abstract: Signal transducers and activators of transcription 6 (STAT6) is an important transcription factor in interleukin (IL)-4 signaling pathway and a key regulator of the type 2 helper T (Th2) cell immune response. Therefore, STAT6 may be an excellent therapeutic target for allergic conditions, including asthma and atopic diseases. Previously, we reported 4-aminopyrimidine-5-carboxamide derivatives as STAT6 inhibitors. To search for novel STAT6 inhibitors, we synthesized fused bicyclic pyrimidine derivatives and identified a 7H-pyrrolo[2,3-d]pyrimidine derivative as a STAT6 inhibitor. Optimization of the pyrrolopyrimidine derivatives led to identification of 2-[4-(4-{[7-(3,5-difluorobenzyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino}phenyl)piperazin-1-yl]acetamide (24, AS1810722) which showed potent STAT6 inhibition and a good CYP3A4 inhibition profile. Compound 24 also inhibited in vitro Th2 differentiation without affecting type 1 helper T (Th1) cell differentiation and eosinophil infiltration in an antigen-induced mouse asthmatic model after oral administration.
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. shinya.nagashima@jp.astellas.com
authors.forename: Shinya
authors.initials: S
authors.lastname: Nagashima
authors.forename: Takeshi
authors.initials: T
authors.lastname: Hondo
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nagata
authors.forename: Takashi
authors.initials: T
authors.lastname: Ogiyama
authors.forename: Jun
authors.initials: J
authors.lastname: Maeda
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Hoshii
authors.forename: Toru
authors.initials: T
authors.lastname: Kontani
authors.forename: Sadao
authors.initials: S
authors.lastname: Kuromitsu
authors.forename: Keiko
authors.initials: K
authors.lastname: Ohga
authors.forename: Masaya
authors.initials: M
authors.lastname: Orita
authors.forename: Kazuki
authors.initials: K
authors.lastname: Ohno
authors.forename: Ayako
authors.initials: A
authors.lastname: Moritomo
authors.forename: Koichi
authors.initials: K
authors.lastname: Shiozuka
authors.forename: Masako
authors.initials: M
authors.lastname: Furutani
authors.forename: Makoto
authors.initials: M
authors.lastname: Takeuchi
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Ohta
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Tsukamoto
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001249:Asthma / Q000188:drug therapy; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D004804:Eosinophils / Q000187:drug effects; D006801:Humans; D007109:Immunity; D051379:Mice; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D011758:Pyrroles / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D050800:STAT6 Transcription Factor / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D018418:Th2 Cells / Q000187:drug effects
chemical_list: D065692:Cytochrome P-450 CYP3A Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; C527741:pyrrolopyrimidine; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human