Discovery of 3-morpholino-imidazole[1,5-a]pyrazine BTK inhibitors for rheumatoid arthritis |
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Authors: | 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 Joseph A. Kozlowski |
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Affiliation: | 1. Department of Early Development and Discovery Sciences, MRL, Merck & Co., Inc., 126 East Lincoln Avenue, Rahway, NJ 07065, USA;2. WuXi PharmaTech Co. Ltd, 288 FuTe Zhong Road, No. 1 Building, WaiGaoQiao Free Trade Zone, Shanghai 200131, PR China |
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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. |
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Keywords: | BTK inhibitor ATP ribose pocket Rheumatoid arthritis Kinase selectivity Immunology |
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