title: Discovery of the macrocycle (9E)-15-(2-(pyrrolidin-1-yl)ethoxy)-7,12,25-trioxa-19,21,24-triaza-tetracyclo[18.3.1.1(2,5).1(14,18)]hexacosa-1(24),2,4,9,14(26),15,17,20,22-nonaene (SB1578), a potent inhibitor of janus kinase 2/fms-like tyrosine kinase-3 (JAK2/FLT3) for the treatment of rheumatoid arthritis.
abstract: Herein, we describe the synthesis and SAR of a series of small molecule macrocycles that selectively inhibit JAK2 kinase within the JAK family and FLT3 kinase. Following a multiparameter optimization of a key aryl ring of the previously described SB1518 (pacritinib), the highly soluble 14l was selected as the optimal compound. Oral efficacy in the murine collagen-induced arthritis (CIA) model for rheumatoid arthritis (RA) supported 14l as a potential treatment for autoimmune diseases and inflammatory disorders such as psoriasis and RA. Compound 14l (SB1578) was progressed into development and is currently undergoing phase 1 clinical trials in healthy volunteers.
authors.affiliation: S BIO Pte. Ltd., 1 Science Park Road, #05-09 The Capricorn, Singapore Science Park II, Singapore 117528. wanthony11@yahoo.com
authors.forename: Anthony D
authors.initials: AD
authors.lastname: William
authors.forename: Angeline C-H
authors.initials: AC
authors.lastname: Lee
authors.forename: Anders
authors.initials: A
authors.lastname: Poulsen
authors.forename: Kee Chuan
authors.initials: KC
authors.lastname: Goh
authors.forename: Babita
authors.initials: B
authors.lastname: Madan
authors.forename: Stefan
authors.initials: S
authors.lastname: Hart
authors.forename: Evelyn
authors.initials: E
authors.lastname: Tan
authors.forename: Haishan
authors.initials: H
authors.lastname: Wang
authors.forename: Harish
authors.initials: H
authors.lastname: Nagaraj
authors.forename: Dizhong
authors.initials: D
authors.lastname: Chen
authors.forename: Chai Ping
authors.initials: CP
authors.lastname: Lee
authors.forename: Eric T
authors.initials: ET
authors.lastname: Sun
authors.forename: Ramesh
authors.initials: R
authors.lastname: Jayaraman
authors.forename: Mohammad Khalid
authors.initials: MK
authors.lastname: Pasha
authors.forename: Kantharaj
authors.initials: K
authors.lastname: Ethirajulu
authors.forename: Jeanette M
authors.initials: JM
authors.lastname: Wood
authors.forename: Brian W
authors.initials: BW
authors.lastname: Dymock
mesh_terms: D000818:Animals; D018501:Antirheumatic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000188:drug therapy; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D002460:Cell Line; D002463:Cell Membrane Permeability; D024043:Collagen Type II; D004285:Dogs; D005260:Female; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000502:physiology; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008861:Microsomes / Q000378:metabolism; D008958:Models, Molecular; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D012995:Solubility; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D053634:TYK2 Kinase / Q000037:antagonists & inhibitors; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors*
chemical_list: C573839:15-(2-(pyrrolidin-1-yl)ethoxy)-7,12,25-trioxa-19,21,24-triazatetracyclo(18.3.1.1(2,5).1(14,18))hexacosa-1(24),2,4,9,14(26),15,17,20,22-nonaene; D018501:Antirheumatic Agents; D024043:Collagen Type II; D006576:Heterocyclic Compounds, 4 or More Rings; D051941:fms-Like Tyrosine Kinase 3; D053614:Janus Kinase 2; D053634:TYK2 Kinase