title: Approaching the active conformation of 1,3-diaminopyrimidine based covalent inhibitors of Bruton's tyrosine kinase for treatment of Rheumatoid arthritis.
abstract: By applying conformational restrictions, we were able to discover highly potent 1,3-diaminopyrimidine based covalent inhibitors of BTK, such as 8a (IC50=3.76 nM), and providing useful information of its active conformation. We are developing these novel small molecule covalent inhibitors of BTK toward oral agents for Rheumatoid arthritis.
authors.affiliation: KBP Biosciences, C201, No. 750, Shunhua Road, Jinan, Shandong Province 250101, China. Electronic address: kbp@kbpbiosciences.com.
authors.forename: Zhenhua
authors.initials: Z
authors.lastname: Huang
authors.affiliation: KBP Biosciences, C201, No. 750, Shunhua Road, Jinan, Shandong Province 250101, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: KBP Biosciences, C201, No. 750, Shunhua Road, Jinan, Shandong Province 250101, China.
authors.forename: Lianzhong
authors.initials: L
authors.lastname: Yan
authors.affiliation: KBP Biosciences, C201, No. 750, Shunhua Road, Jinan, Shandong Province 250101, China.
authors.forename: Guizhen
authors.initials: G
authors.lastname: Zhong
authors.affiliation: KBP Biosciences, C201, No. 750, Shunhua Road, Jinan, Shandong Province 250101, China.
authors.forename: Linqi
authors.initials: L
authors.lastname: Zhang
authors.affiliation: KBP Biosciences, C201, No. 750, Shunhua Road, Jinan, Shandong Province 250101, China.
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Tan
authors.affiliation: KBP Biosciences, C201, No. 750, Shunhua Road, Jinan, Shandong Province 250101, China.
authors.forename: Yanli
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000378:metabolism; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008968:Molecular Conformation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: C000612205:1,3-diaminopyrimidine; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human
keywords: 1,3-Diamino-pyrimidine; Bruton’s tyrosine kinase (BTK); Collagen-induced arthritis (CIA); Rheumatoid arthritis (RA)