title: Discovery and SAR of pyrrolo[2,1-f][1,2,4]triazin-4-amines as potent and selective PI3Kδ inhibitors.
abstract: Aberrant Class I PI3K signaling is a key factor contributing to many immunological disorders and cancers. We have identified 4-amino pyrrolotriazine as a novel chemotype that selectively inhibits PI3Kδ signaling despite not binding to the specificity pocket of PI3Kδ isoform. Structure activity relationship (SAR) led to the identification of compound 30 that demonstrated efficacy in mouse Keyhole Limpet Hemocyanin (KLH) and collagen induced arthritis (CIA) models.
authors.affiliation: Discovery chemistry, Research & Development, Bristol-Myers Squibb Company, Route 206 & Province Line Road, Princeton, NJ 08534, United States. Electronic address: rajeev.bhide@bms.com.
authors.forename: Rajeev S
authors.initials: RS
authors.lastname: Bhide
authors.affiliation: Discovery chemistry, Research & Development, Bristol-Myers Squibb Company, Route 206 & Province Line Road, Princeton, NJ 08534, United States.
authors.forename: James
authors.initials: J
authors.lastname: Neels
authors.affiliation: Discovery chemistry, Research & Development, Bristol-Myers Squibb Company, Route 206 & Province Line Road, Princeton, NJ 08534, United States.
authors.forename: Lan-Ying
authors.initials: LY
authors.lastname: Qin
authors.affiliation: Discovery chemistry, Research & Development, Bristol-Myers Squibb Company, Route 206 & Province Line Road, Princeton, NJ 08534, United States.
authors.forename: Zheming
authors.initials: Z
authors.lastname: Ruan
authors.affiliation: Discovery chemistry, Research & Development, Bristol-Myers Squibb Company, Route 206 & Province Line Road, Princeton, NJ 08534, United States.
authors.forename: Sylwia
authors.initials: S
authors.lastname: Stachura
authors.affiliation: Molecular structure and design, Research & Development, Bristol-Myers Squibb Company, Route 206 & Province Line Road, Princeton, NJ 08534, United States.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Weigelt
authors.affiliation: Molecular structure and design, Research & Development, Bristol-Myers Squibb Company, Route 206 & Province Line Road, Princeton, NJ 08534, United States.
authors.forename: John S
authors.initials: JS
authors.lastname: Sack
authors.affiliation: PCO discovery, Research & Development, Bristol-Myers Squibb Company, Route 206 & Province Line Road, Princeton, NJ 08534, United States.
authors.forename: Kevin
authors.initials: K
authors.lastname: Stefanski
authors.affiliation: PCO discovery, Research & Development, Bristol-Myers Squibb Company, Route 206 & Province Line Road, Princeton, NJ 08534, United States.
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Gu
authors.affiliation: Immunoscience biology, Research & Development, Bristol-Myers Squibb Company, Route 206 & Province Line Road, Princeton, NJ 08534, United States.
authors.forename: Jenny H
authors.initials: JH
authors.lastname: Xie
authors.affiliation: Immunoscience biology, Research & Development, Bristol-Myers Squibb Company, Route 206 & Province Line Road, Princeton, NJ 08534, United States.
authors.forename: Christine B
authors.initials: CB
authors.lastname: Goldstine
authors.affiliation: Immunoscience biology, Research & Development, Bristol-Myers Squibb Company, Route 206 & Province Line Road, Princeton, NJ 08534, United States.
authors.forename: Stacey
authors.initials: S
authors.lastname: Skala
authors.affiliation: Immunoscience biology, Research & Development, Bristol-Myers Squibb Company, Route 206 & Province Line Road, Princeton, NJ 08534, United States.
authors.forename: Donna L
authors.initials: DL
authors.lastname: Pedicord
authors.affiliation: PCO discovery, Research & Development, Bristol-Myers Squibb Company, Route 206 & Province Line Road, Princeton, NJ 08534, United States.
authors.forename: Stefan
authors.initials: S
authors.lastname: Ruepp
authors.affiliation: Discovery chemistry, Research & Development, Bristol-Myers Squibb Company, Route 206 & Province Line Road, Princeton, NJ 08534, United States.
authors.forename: T G Murali
authors.initials: TG
authors.lastname: Dhar
authors.affiliation: Discovery chemistry, Research & Development, Bristol-Myers Squibb Company, Route 206 & Province Line Road, Princeton, NJ 08534, United States.
authors.forename: Percy H
authors.initials: PH
authors.lastname: Carter
authors.affiliation: Immunoscience biology, Research & Development, Bristol-Myers Squibb Company, Route 206 & Province Line Road, Princeton, NJ 08534, United States.
authors.forename: Luisa M
authors.initials: LM
authors.lastname: Salter-Cid
authors.affiliation: Discovery chemistry, Research & Development, Bristol-Myers Squibb Company, Route 206 & Province Line Road, Princeton, NJ 08534, United States.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Poss
authors.affiliation: Immunoscience biology, Research & Development, Bristol-Myers Squibb Company, Route 206 & Province Line Road, Princeton, NJ 08534, United States.
authors.forename: Paul
authors.initials: P
authors.lastname: Davies
mesh_terms: D000588:Amines / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D000818:Animals; D001168:Arthritis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D001665:Binding Sites; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D020128:Inhibitory Concentration 50; D051379:Mice; D062105:Molecular Docking Simulation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011485:Protein Binding; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D014227:Triazines / Q000737:chemistry*
chemical_list: D000588:Amines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors; D014227:Triazines
keywords: PI3Kδ; Phosphatidylinositol-3 kinases; Pyrrolo[2,1-f][1,2,4]triazin-4-amine; Rheumatoid arthritis