title: Discovery of 7-(3-(piperazin-1-yl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine derivatives as highly potent and selective PI3Kδ inhibitors.
abstract: As demonstrated in preclinical animal models, the disruption of PI3Kδ expression or its activity leads to a decrease in inflammatory and immune responses. Therefore, inhibition of PI3Kδ may provide an alternative treatment for autoimmune diseases, such as RA, SLE, and respiratory ailments. Herein, we disclose the identification of 7-(3-(piperazin-1-yl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine derivatives as highly potent, selective and orally bioavailable PI3Kδ inhibitors. The lead compound demonstrated efficacy in an in vivo mouse KLH model.
authors.affiliation: Bristol-Myers Squibb, Rt. 206 & Province Line Road, Princeton, NJ 08540, USA. Electronic address: lan-ying.qin@bms.com.
authors.forename: Lan-Ying
authors.initials: LY
authors.lastname: Qin
authors.affiliation: Bristol-Myers Squibb, Rt. 206 & Province Line Road, Princeton, NJ 08540, USA.
authors.forename: Zheming
authors.initials: Z
authors.lastname: Ruan
authors.affiliation: Bristol-Myers Squibb, Rt. 206 & Province Line Road, Princeton, NJ 08540, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Cherney
authors.affiliation: Bristol-Myers Squibb, Rt. 206 & Province Line Road, Princeton, NJ 08540, USA.
authors.forename: T G Murali
authors.initials: TGM
authors.lastname: Dhar
authors.affiliation: Bristol-Myers Squibb, Rt. 206 & Province Line Road, Princeton, NJ 08540, USA.
authors.forename: James
authors.initials: J
authors.lastname: Neels
authors.affiliation: Bristol-Myers Squibb, Rt. 206 & Province Line Road, Princeton, NJ 08540, USA.
authors.forename: Carolyn A
authors.initials: CA
authors.lastname: Weigelt
authors.affiliation: Bristol-Myers Squibb, Rt. 206 & Province Line Road, Princeton, NJ 08540, USA.
authors.forename: John S
authors.initials: JS
authors.lastname: Sack
authors.affiliation: Bristol-Myers Squibb, Rt. 206 & Province Line Road, Princeton, NJ 08540, USA.
authors.forename: Anurag S
authors.initials: AS
authors.lastname: Srivastava
authors.affiliation: Bristol-Myers Squibb, Rt. 206 & Province Line Road, Princeton, NJ 08540, USA.
authors.forename: Lyndon A M
authors.initials: LAM
authors.lastname: Cornelius
authors.affiliation: Bristol-Myers Squibb, Rt. 206 & Province Line Road, Princeton, NJ 08540, USA.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Tino
authors.affiliation: Bristol-Myers Squibb, Rt. 206 & Province Line Road, Princeton, NJ 08540, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Stefanski
authors.affiliation: Bristol-Myers Squibb, Rt. 206 & Province Line Road, Princeton, NJ 08540, USA.
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Gu
authors.affiliation: Bristol-Myers Squibb, Rt. 206 & Province Line Road, Princeton, NJ 08540, USA.
authors.forename: Jenny
authors.initials: J
authors.lastname: Xie
authors.affiliation: Bristol-Myers Squibb, Rt. 206 & Province Line Road, Princeton, NJ 08540, USA.
authors.forename: Vojkan
authors.initials: V
authors.lastname: Susulic
authors.affiliation: Bristol-Myers Squibb, Rt. 206 & Province Line Road, Princeton, NJ 08540, USA.
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Yang
authors.affiliation: Bristol-Myers Squibb, Rt. 206 & Province Line Road, Princeton, NJ 08540, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Yarde-Chinn
authors.affiliation: Bristol-Myers Squibb, Rt. 206 & Province Line Road, Princeton, NJ 08540, USA.
authors.forename: Stacey
authors.initials: S
authors.lastname: Skala
authors.affiliation: Bristol-Myers Squibb, Rt. 206 & Province Line Road, Princeton, NJ 08540, USA.
authors.forename: Ruth
authors.initials: R
authors.lastname: Bosnius
authors.affiliation: Bristol-Myers Squibb, Rt. 206 & Province Line Road, Princeton, NJ 08540, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Goldstein
authors.affiliation: Bristol-Myers Squibb, Rt. 206 & Province Line Road, Princeton, NJ 08540, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Davies
authors.affiliation: Bristol-Myers Squibb, Rt. 206 & Province Line Road, Princeton, NJ 08540, USA.
authors.forename: Stefan
authors.initials: S
authors.lastname: Ruepp
authors.affiliation: Bristol-Myers Squibb, Rt. 206 & Province Line Road, Princeton, NJ 08540, USA.
authors.forename: Luisa
authors.initials: L
authors.lastname: Salter-Cid
authors.affiliation: Bristol-Myers Squibb, Rt. 206 & Province Line Road, Princeton, NJ 08540, USA.
authors.forename: Rajeev S
authors.initials: RS
authors.lastname: Bhide
authors.affiliation: Bristol-Myers Squibb, Rt. 206 & Province Line Road, Princeton, NJ 08540, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Poss
mesh_terms: D000588:Amines / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D000818:Animals; D001327:Autoimmune Diseases / Q000188:drug therapy; D001665:Binding Sites; D058534:Class I Phosphatidylinositol 3-Kinases; D018360:Crystallography, X-Ray; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D006801:Humans; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D062105:Molecular Docking Simulation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D000077489:Piperazine; D010879:Piperazines / Q000737:chemistry; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D014227:Triazines / Q000737:chemistry
chemical_list: D000588:Amines; D058534:Class I Phosphatidylinositol 3-Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D000077489:Piperazine; D010879:Piperazines; D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors; D014227:Triazines; C421683:Pik3cd protein, mouse
keywords: 7-Phenylpyrrolo[2,1-f][1,2,4]triazin-4-amine; Autoimmune diseases; PI3Kδ; Phosphoinositide 3-kinases; Rheumatoid arthritis