Identification of (R)-(2-Chloro-3-(trifluoromethyl)phenyl)(1-(5-fluoropyridin-2-yl)-4-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methanone (JNJ 54166060), a Small Molecule Antagonist of the P2X7 receptor,Journal of Medicinal Chemistry

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Identification of (R)-(2-Chloro-3-(trifluoromethyl)phenyl)(1-(5-fluoropyridin-2-yl)-4-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methanone (JNJ 54166060), a Small Molecule Antagonist of the P2X7 receptor
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2016-09-08 00:00:00 , DOI: 10.1021/acs.jmedchem.6b00989
Devin M. Swanson ₁ , Brad M. Savall ₁ , Kevin J. Coe ₁ , Freddy Schoetens ₁ , Tatiana Koudriakova ₁ , Judith Skaptason ₁ , Jessica Wall ₁ , Jason Rech ₁ , Xiahou Deng ₁ , Meri De Angelis ₂ , Anita Everson ₁ , Brian Lord ₁ , Qi Wang ₁ , Hong Ao ₁ , Brian Scott ₁ , Kia Sepassi ₁ , Timothy W. Lovenberg ₁ , Nicholas I. Carruthers ₁ , Anindya Bhattacharya ₁ , Michael A. Letavic ₁

Affiliation

The synthesis and SAR of a series of 4,5,6,7-tetrahydro-imidazo[4,5-c]pyridine P2X7 antagonists are described. Addressing P2X7 affinity and liver microsomal stability issues encountered with this template afforded methyl substituted 4,5,6,7-tetrahydro-imidazo[4,5-c]pyridines ultimately leading to the identification of 1 (JNJ 54166060). 1 is a potent P2X7 antagonist with an ED₅₀ = 2.3 mg/kg in rats, high oral bioavailability and low-moderate clearance in preclinical species, acceptable safety margins in rats, and a predicted human dose of 120 mg of QD. Additionally, 1 possesses a unique CYP profile and was found to be a regioselective inhibitor of midazolam CYP3A metabolism.

中文翻译：

（R）-（2-氯-3-（三氟甲基）苯基）（1-（5-氟吡啶-2-基）-4-甲基-6,7-二氢-1 H-咪唑[4,5- c ] pyridin-5（4 H）-yl）methanone（JNJ 54166060），P2X7受体的小分子拮抗剂

描述了一系列4,5,6,7-四氢咪唑并[4,5- c ]吡啶P2X7拮抗剂的合成和SAR 。解决此模板遇到的P2X7亲和力和肝微粒体稳定性问题，提供了甲基取代的4,5,6,7-四氢咪唑并[4,5- c ]吡啶，最终导致1的鉴定（JNJ 54166060）。1是一种有效的P2X7拮抗剂，在大鼠中的ED ₅₀ = 2.3 mg / kg，在临床前物种中具有较高的口服生物利用度和低中度清除率，在大鼠中具有可接受的安全范围，并且预计的人类剂量为120 mg QD。此外，1具有独特的CYP谱，被发现是咪达唑仑CYP3A代谢的区域选择性抑制剂。

更新日期：2016-09-08

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