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.

中文翻译：

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发现和优化的3-（2-（Pyrazolo [1,5 - a ]嘧啶-6-基）乙炔基）苯甲酰胺作为新型选择性和口服生物利用盘状结构域受体1（DDR1）抑制剂。

Discoidin域受体1（DDR1）是新的抗癌药物发现的新兴潜在分子靶标。我们发现了一系列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可生物利用的DDR1抑制剂。两种最有希望的化合物（7rh和7rj）抑制DDR1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7rh与DDR1的K _d绑定值为0.6 nM，而对其他455种激酶的效价却明显较低。7rh的S（35）和S（10）选择性得分分别为0.035和0.008。该化合物还有效抑制表达高水平DDR1的癌细胞的增殖，并强烈抑制癌细胞的侵袭，粘附和致瘤性。初步的药代动力学研究表明，它们具有良好的PK分布，口服生物利用度分别为67.4％和56.2％。