Identification of imidazo-pyrrolopyridines as novel and potent JAK1 inhibitors.
Article Details
- CitationCopy to clipboard
Kulagowski JJ, Blair W, Bull RJ, Chang C, Deshmukh G, Dyke HJ, Eigenbrot C, Ghilardi N, Gibbons P, Harrison TK, Hewitt PR, Liimatta M, Hurley CA, Johnson A, Johnson T, Kenny JR, Bir Kohli P, Maxey RJ, Mendonca R, Mortara K, Murray J, Narukulla R, Shia S, Steffek M, Ubhayakar S, Ultsch M, van Abbema A, Ward SI, Waszkowycz B, Zak M
Identification of imidazo-pyrrolopyridines as novel and potent JAK1 inhibitors.
J Med Chem. 2012 Jun 28;55(12):5901-21. doi: 10.1021/jm300438j. Epub 2012 Jun 11.
- PubMed ID
- 22591402 [ View in PubMed]
- Abstract
A therapeutic rationale is proposed for the treatment of inflammatory diseases, such as rheumatoid arthritis (RA), by specific targeting of the JAK1 pathway. Examination of the preferred binding conformation of clinically effective, pan-JAK inhibitor 1 led to identification of a novel, tricyclic hinge binding scaffold 3. Exploration of SAR through a series of cycloamino and cycloalkylamino analogues demonstrated this template to be highly tolerant of substitution, with a predisposition to moderate selectivity for the JAK1 isoform over JAK2. This study culminated in the identification of subnanomolar JAK1 inhibitors such as 22 and 49, having excellent cell potency, good rat pharmacokinetic characteristics, and excellent kinase selectivity. Determination of the binding modes of the series in JAK1 and JAK2 by X-ray crystallography supported the design of analogues to enhance affinity and selectivity.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Ruxolitinib Tyrosine-protein kinase JAK2 IC 50 (nM) 2.8 N/A N/A Details Tofacitinib Non-receptor tyrosine-protein kinase TYK2 Ki (nM) 7.8 N/A N/A Details Tofacitinib Non-receptor tyrosine-protein kinase TYK2 Ki (nM) 4.39 N/A N/A Details Tofacitinib Tyrosine-protein kinase JAK2 Ki (nM) 0.7 N/A N/A Details Tofacitinib Tyrosine-protein kinase JAK2 Ki (nM) 0.99 N/A N/A Details Tofacitinib Tyrosine-protein kinase JAK3 Ki (nM) 0.4 N/A N/A Details Tofacitinib Tyrosine-protein kinase JAK3 Ki (nM) 0.24 N/A N/A Details