Discovery of 3-morpholino-imidazole[1,5-a]pyrazine BTK inhibitors for rheumatoid arthritis

Sobhana Babu Boga; Abdul-Basit Alhassan; Jian Liu; Deodial Guiadeen; Arto Krikorian; Xiaolei Gao; James Wang; Younong Yu; Rajan Anand; Shilan Liu; Chundao Yang; Hao Wu; Jiaqiang Cai; Hugh Zhu; Jagdish Desai; Kevin Maloney; Ying-Duo Gao; Thierry O Fischmann; Jeremy Presland; My Mansueto; Zangwei Xu; Erica Leccese; Ian Knemeyer; Charles G Garlisi; Nathan Bays; Peter Stivers; Philip E Brandish; Alexandra Hicks; Alan Cooper; Ronald M Kim; Joseph A Kozlowski

doi:10.1016/j.bmcl.2017.03.040

Discovery of 3-morpholino-imidazole[1,5-a]pyrazine BTK inhibitors for rheumatoid arthritis

Bioorg Med Chem Lett. 2017 Aug 15;27(16):3939-3943. doi: 10.1016/j.bmcl.2017.03.040. Epub 2017 Mar 18.

Authors

Sobhana Babu Boga¹, Abdul-Basit Alhassan², Jian Liu², Deodial Guiadeen², Arto Krikorian², Xiaolei Gao², James Wang², Younong Yu², Rajan Anand², Shilan Liu³, Chundao Yang³, Hao Wu³, Jiaqiang Cai³, Hugh Zhu², Jagdish Desai², Kevin Maloney², Ying-Duo Gao², Thierry O Fischmann², Jeremy Presland², My Mansueto², Zangwei Xu², Erica Leccese², Ian Knemeyer², Charles G Garlisi², Nathan Bays², Peter Stivers², Philip E Brandish², Alexandra Hicks², Alan Cooper², Ronald M Kim², Joseph A Kozlowski²

Affiliations

¹ Department of Early Development and Discovery Sciences, MRL, Merck & Co., Inc., 126 East Lincoln Avenue, Rahway, NJ 07065, USA. Electronic address: sobhana.babu.boga@merck.com.
² Department of Early Development and Discovery Sciences, MRL, Merck & Co., Inc., 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
³ WuXi PharmaTech Co. Ltd, 288 FuTe Zhong Road, No. 1 Building, WaiGaoQiao Free Trade Zone, Shanghai 200131, PR China.

PMID: 28720503
DOI: 10.1016/j.bmcl.2017.03.040

Abstract

8-Amino-imidazo[1,5-a]pyrazine-based Bruton's tyrosine kinase (BTK) inhibitors, such as 6, exhibited potent inhibition of BTK but required improvements in both kinase and hERG selectivity (Liu et al., 2016; Gao et al., 2017). In an effort to maintain the inhibitory activity of these analogs and improve their selectivity profiles, we carried out SAR exploration of groups at the 3-position of pyrazine compound 6. This effort led to the discovery of the morpholine group as an optimized pharmacophore. Compounds 13, 23 and 38 displayed excellent BTK potencies, kinase and hERG selectivities, and pharmacokinetic profiles.

Keywords: ATP ribose pocket; BTK inhibitor; Immunology; Kinase selectivity; Rheumatoid arthritis.

MeSH terms

Arthritis, Rheumatoid / drug therapy*
Arthritis, Rheumatoid / metabolism
Dose-Response Relationship, Drug
Drug Discovery*
Humans
Imidazoles / chemical synthesis
Imidazoles / chemistry
Imidazoles / pharmacology*
Leukocytes, Mononuclear / drug effects
Leukocytes, Mononuclear / metabolism
Models, Molecular
Molecular Structure
Morpholines / chemical synthesis
Morpholines / chemistry
Morpholines / pharmacology*
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Protein-Tyrosine Kinases / antagonists & inhibitors*
Protein-Tyrosine Kinases / metabolism
Structure-Activity Relationship
Transcriptional Regulator ERG / antagonists & inhibitors
Transcriptional Regulator ERG / metabolism

Substances

3-morpholino-imidazole(1,5-a)pyrazine
ERG protein, human
Imidazoles
Morpholines
Protein Kinase Inhibitors
Transcriptional Regulator ERG
Protein-Tyrosine Kinases