Discovery, Structure–Activity Relationships, and In Vivo Evaluation of Novel Aryl Amides as Brain Penetrant Adaptor Protein 2-Associated Kinase 1 (AAK1) Inhibitors for the Treatment of Neuropathic Pain,Journal of Medicinal Chemistry

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Discovery, Structure–Activity Relationships, and In Vivo Evaluation of Novel Aryl Amides as Brain Penetrant Adaptor Protein 2-Associated Kinase 1 (AAK1) Inhibitors for the Treatment of Neuropathic Pain
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-07-16 , DOI: 10.1021/acs.jmedchem.1c00472
Richard A Hartz ₁ , Vijay T Ahuja ₁ , Susheel J Nara ₂ , C M Vijaya Kumar ₂ , Jeffrey M Brown ₃ , Linda J Bristow ₃ , Ramkumar Rajamani ₄ , Jodi K Muckelbauer ₅ , Daniel Camac ₅ , Susan E Kiefer ₆ , Lisa Hunihan ₃ , Michael Gulianello ₃ , Martin Lewis ₃ , Amy Easton ₃ , Jonathan S Lippy ₇ , Neha Surti ₇ , Sreenivasulu N Pattipati ₂ , Manoj Dokania ₂ , Saravanan Elavazhagan ₂ , Kumaran Dandapani ₂ , Brian D Hamman ₈ , Jason Allen ₈ , Walter Kostich ₃ , Joanne J Bronson ₁ , John E Macor ₁ , Carolyn D Dzierba ₁

Affiliation

Department of Small Molecule Drug Discovery, Bristol Myers Squibb Company, Research and Development, Wallingford, Connecticut 06492, United States.
Biocon-Bristol Myers Squibb Research and Development Center, Biocon Park, Plot No. 2 & 3, Bommasandra Phase IV, Jigani Link Road, Bangalore 560099, India.
Department of Neuroscience Discovery Biology, Bristol Myers Squibb Company, Research and Development, Wallingford, Connecticut 06492, United States.
Department of Molecular Structure and Design, Bristol Myers Squibb Company, Research and Development, Wallingford, Connecticut 06492, United States.
Department of Molecular Structure and Design, Bristol Myers Squibb Company, Research and Development, Princeton, New Jersey 08543, United States.
Department of Protein Science, Bristol Myers Squibb Company, Research and Development, Princeton, New Jersey 08543, United States.
Department of Lead Evaluation, Bristol Myers Squibb Company, Research and Development, Princeton, New Jersey 08543, United States.
Lexicon Pharmaceuticals, 8800 Technology Forest Place, The Woodlands, Texas 77381, United States.

Effective treatment of chronic pain, in particular neuropathic pain, without the side effects that often accompany currently available treatment options is an area of significant unmet medical need. A phenotypic screen of mouse gene knockouts led to the discovery that adaptor protein 2-associated kinase 1 (AAK1) is a potential therapeutic target for neuropathic pain. The synthesis and optimization of structure–activity relationships of a series of aryl amide-based AAK1 inhibitors led to the identification of 59, a brain penetrant, AAK1-selective inhibitor that proved to be a valuable tool compound. Compound 59 was evaluated in mice for the inhibition of μ2 phosphorylation. Studies conducted with 59 in pain models demonstrated that this compound was efficacious in the phase II formalin model for persistent pain and the chronic-constriction-injury-induced model for neuropathic pain in rats. These results suggest that AAK1 inhibition is a promising approach for the treatment of neuropathic pain.

中文翻译：

新型芳基酰胺作为脑渗透接头蛋白 2 相关激酶 1 (AAK1) 抑制剂治疗神经性疼痛的发现、结构-活性关系和体内评价

有效治疗慢性疼痛，特别是神经性疼痛，没有通常伴随当前可用治疗选择的副作用，是一个显着未满足的医疗需求领域。小鼠基因敲除的表型筛选导致发现接头蛋白 2 相关激酶 1 (AAK1) 是神经性疼痛的潜在治疗靶点。一系列基于芳基酰胺的 AAK1 抑制剂的构效关系的合成和优化导致59的鉴定，这是一种脑渗透性 AAK1 选择性抑制剂，被证明是一种有价值的工具化合物。在小鼠中评估了化合物59对 μ2 磷酸化的抑制。对59 人进行的研究在疼痛模型中证明该化合物在持续性疼痛的 II 期福尔马林模型和大鼠神经性疼痛的慢性收缩损伤诱导模型中是有效的。这些结果表明 AAK1 抑制是治疗神经性疼痛的一种有前途的方法。

更新日期：2021-08-12

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