Discovery and Optimization of 3-(2-(Pyrazolo[1,5-a]pyrimidin-6-yl)-ethynyl)benzamides as Novel Selective and Orally Bioavailable Discoidin Domain Receptor 1 (DDR1) Inhibitors
Discovery and Optimization of 3-(2-(Pyrazolo[1,5-a]pyrimidin-6-yl)-ethynyl)benzamides as Novel Selective and Orally Bioavailable Discoidin Domain Receptor 1 (DDR1) Inhibitors
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DOI：
10.1021/jm301824k
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发表时间：
2013-04-25
影响因子：
7.3
通讯作者：
Ding, Ke
中科院分区：
文献类型：
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作者：
Gao, Mingshan;Duan, Lei;Ding, Ke
盘状结构域受体1（DDR 1）是一个新兴的潜在的分子靶点，为新的抗癌药物发现。我们已经发现了一系列3-（2-（吡唑并[1，5-a]嘧啶-6-基）乙炔基）-苯甲酰胺，它们是选择性的和口服生物可利用的DDR 1抑制剂。两种最有前途的化合物（7 rh和7 rj）抑制DDR 1的酶活性，IC 50值分别为6.8和7.0 nM，但在抑制DDR2、Bcr-Abl和c-Kit的激酶活性方面的效力明显较低。进一步的研究表明，7 rh与DDR 1结合的Kd值为0.6 nM，而它对其他455种测试的激酶的效力明显较低。7 rh的S（35）和S（10）选择性评分分别为0.035和0.008。这些化合物还有效地抑制表达高水平DDR 1的癌细胞的增殖，并强烈抑制癌细胞侵袭、粘附和致瘤性。初步药代动力学研究表明，它们具有良好的PK特征，口服生物利用度分别为67.4%和56.2%。
Discoidin domain receptor 1 (DDR1) is an emerging potential molecular target for new anticancer drug discovery. We have discovered a series of 3-(2-(pyrazolo[1,5-a]pyrimidin-6-yl) ethynyl)-benzamides that are selective and orally bioavailable DDR1 inhibitors. The two most promising compounds (7rh and 7rj) inhibited the enzymatic activity of DDR1, with IC50 values of 6.8 and 7.0 nM, respectively, but were significantly less potent in suppressing the kinase activities of DDR2, Bcr-Abl, and c-Kit. Further study revealed that 7rh bound with DDR1 with a K-d value of 0.6 nM, while it was significantly less potent to the other 455 kinases tested. The S(35) and S(10) selectivity scores of 7rh were 0.035 and 0.008, respectively. The compounds also potently inhibited the proliferation of cancer cells expressing high levels of DDR1 and strongly suppressed cancer cell invasion, adhesion, and tumorigenicity. Preliminary pharmacokinetic studies suggested that they possessed good PK profiles, with oral bioavailabilities of 67.4% and 56.2%, respectively.