Discovery of the c-Jun N-Terminal Kinase Inhibitor CC-90001,Journal of Medicinal Chemistry

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Discovery of the c-Jun N-Terminal Kinase Inhibitor CC-90001
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-12-13 , DOI: 10.1021/acs.jmedchem.1c01716
Mark A Nagy ₁ , Robert Hilgraf ₁ , Deborah S Mortensen ₁ , Jan Elsner ₁ , Stephen Norris ₁ , Jayashree Tikhe ₁ , Won Yoon ₁ , David Paisner ₁ , Mercedes Delgado ₁ , Paul Erdman ₁ , Jason Haelewyn ₁ , Godrej Khambatta ₁ , Li Xu ₁ , William J Romanow ₁ , Kevin Condroski ₁ , Sogole Bahmanyar ₁ , Meg McCarrick ₁ , Brent Benish ₁ , Kate Blease ₁ , Laurie LeBrun ₁ , Mehran F Moghaddam ₁ , Julius Apuy ₁ , Stacie S Canan ₁ , Brydon L Bennett ₁ , Yoshitaka Satoh ₁

Affiliation

As a result of emerging biological data suggesting that within the c-Jun N-terminal kinase (JNK) family, JNK1 and not JNK2 or JNK3 may be primarily responsible for fibrosis pathology, we sought to identify JNK inhibitors with an increased JNK1 bias relative to our previous clinical compound tanzisertib (CC-930). This manuscript reports the synthesis and structure–activity relationship (SAR) studies for a novel series of JNK inhibitors demonstrating an increased JNK1 bias. SAR optimization on a series of 2,4-dialkylamino-pyrimidine-5-carboxamides resulted in the identification of compounds possessing low nanomolar JNK inhibitory potency, overall kinome selectivity, and the ability to inhibit cellular phosphorylation of the direct JNK substrate c-Jun. Optimization of physicochemical properties in this series resulted in compounds that demonstrated excellent systemic exposure following oral dosing, enabling in vivo efficacy studies and the selection of a candidate for clinical development, CC-90001, which is currently in clinical trials (Phase II) in patients with idiopathic pulmonary fibrosis (NCT03142191).

中文翻译：

c-Jun N-末端激酶抑制剂 CC-90001 的发现

由于新出现的生物学数据表明在 c-Jun N-末端激酶 (JNK) 家族中，JNK1 而不是 JNK2 或 JNK3 可能主要负责纤维化病理学，我们试图确定 JNK 抑制剂相对于 JNK1 偏倚增加我们以前的临床化合物 tanzisertib (CC-930)。这份手稿报告了一系列新型 JNK 抑制剂的合成和构效关系 (SAR) 研究，证明 JNK1 偏倚增加。对一系列 2,4-二烷基氨基-嘧啶-5-甲酰胺的 SAR 优化导致鉴定出具有低纳摩尔 JNK 抑制效力、整体激酶组选择性和抑制直接 JNK 底物 c-Jun 的细胞磷酸化能力的化合物。CC-90001，目前处于特发性肺纤维化患者的临床试验（II 期）（NCT03142191）。

更新日期：2021-12-23

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