title: Purine derivatives as potent Bruton's tyrosine kinase (BTK) inhibitors for autoimmune diseases.
abstract: Investigation of various heterocyclic core isosteres of imidazopyrazines 1 & 2 yielded purine derivatives 3 & 8 as potent and selective BTK inhibitors. Subsequent SAR studies of the purine series led to the discovery of 20 as a leading compound. Compound 20 is very selective when screened against a panel of 400 kinases and is a potent inhibitor in cellular assays of human B cell function including B-Cell proliferation and CD86 cell surface expression and exhibited in vivo efficacy in a mouse PCA model. Its X-ray co-crystal structure with BTK shows that the high selectivity is gained from filling a BTK specific lipophilic pocket. However, physical and ADME properties leading to low oral exposure hindered further development.
authors.affiliation: Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, NJ 08543-4000, United States. Electronic address: qing.shi@bms.com.
authors.forename: Qing
authors.initials: Q
authors.lastname: Shi
authors.affiliation: Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, NJ 08543-4000, United States.
authors.forename: Andrew
authors.initials: A
authors.lastname: Tebben
authors.affiliation: Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, NJ 08543-4000, United States.
authors.forename: Alaric J
authors.initials: AJ
authors.lastname: Dyckman
authors.affiliation: Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, NJ 08543-4000, United States.
authors.forename: Hedy
authors.initials: H
authors.lastname: Li
authors.affiliation: Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, NJ 08543-4000, United States.
authors.forename: Chunjian
authors.initials: C
authors.lastname: Liu
authors.affiliation: Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, NJ 08543-4000, United States.
authors.forename: James
authors.initials: J
authors.lastname: Lin
authors.affiliation: Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, NJ 08543-4000, United States.
authors.forename: Steve
authors.initials: S
authors.lastname: Spergel
authors.affiliation: Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, NJ 08543-4000, United States.
authors.forename: James R
authors.initials: JR
authors.lastname: Burke
authors.affiliation: Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, NJ 08543-4000, United States.
authors.forename: Kim W
authors.initials: KW
authors.lastname: McIntyre
authors.affiliation: Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, NJ 08543-4000, United States.
authors.forename: Gilbert C
authors.initials: GC
authors.lastname: Olini
authors.affiliation: Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, NJ 08543-4000, United States.
authors.forename: Joann
authors.initials: J
authors.lastname: Strnad
authors.affiliation: Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, NJ 08543-4000, United States.
authors.forename: Neha
authors.initials: N
authors.lastname: Surti
authors.affiliation: Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, NJ 08543-4000, United States.
authors.forename: Jodi K
authors.initials: JK
authors.lastname: Muckelbauer
authors.affiliation: Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, NJ 08543-4000, United States.
authors.forename: Chiehying
authors.initials: C
authors.lastname: Chang
authors.affiliation: Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, NJ 08543-4000, United States.
authors.forename: Yongmi
authors.initials: Y
authors.lastname: An
authors.affiliation: Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, NJ 08543-4000, United States.
authors.forename: Lin
authors.initials: L
authors.lastname: Cheng
authors.affiliation: Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, NJ 08543-4000, United States.
authors.forename: Qian
authors.initials: Q
authors.lastname: Ruan
authors.affiliation: Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, NJ 08543-4000, United States.
authors.forename: Katerina
authors.initials: K
authors.lastname: Leftheris
authors.affiliation: Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, NJ 08543-4000, United States.
authors.forename: Percy H
authors.initials: PH
authors.lastname: Carter
authors.affiliation: Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, NJ 08543-4000, United States.
authors.forename: Joseph
authors.initials: J
authors.lastname: Tino
authors.affiliation: Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, NJ 08543-4000, United States. Electronic address: george.delucca@bms.com.
authors.forename: George V
authors.initials: GV
authors.lastname: De Lucca
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D001327:Autoimmune Diseases / Q000188:drug therapy / Q000201:enzymology; D001402:B-Lymphocytes / Q000187:drug effects; D018360:Crystallography, X-Ray; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D010323:Passive Cutaneous Anaphylaxis / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011687:Purines / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats
chemical_list: D047428:Protein Kinase Inhibitors; D011687:Purines; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000625951:Btk protein, mouse
keywords: Autoimmune diseases; BTK; Purine