Discovery of Potent, Selective, and Peripherally Restricted Pan-Trk Kinase Inhibitors for the Treatment of Pain

被引：31

作者：

Bagal, Sharan K. ^{[1
]}

Andrews, Mark ^{[4
]}

Bechle, Bruce M. ^{[5
]}

Bian, Jianwei ^{[5
]}

Bilsland, James ^{[3
]}

Blakemore, David C. ^{[1
]}

Braganza, John F. ^{[6
]}

Bungay, Peter J. ^{[2
]}

Corbett, Matthew S. ^{[5
]}

Cronin, Ciaran N. ^{[6
]}

Cui, Jingrong Jean ^{[6
]}

Dias, Rebecca ^{[3
]}

Flanagan, Neil J. ^{[3
]}

Greasley, Samantha E. ^{[6
]}

Grimley, Rachel ^{[3
]}

James, Kim ^{[7
]}

Johnson, Eric ^{[6
]}

Kitching, Linda ^{[3
]}

Kraus, Michelle L. ^{[6
]}

McAlpine, Indrawan ^{[6
]}

Nagata, Asako ^{[6
]}

Ninkovic, Sacha ^{[6
]}

Omoto, Kiyoyuki ^{[1
]}

Scales, Stephanie ^{[6
]}

Skerratt, Sarah E. ^{[1
]}

Sun, Jianmin ^{[5
]}

Tran-Dube, Michelle ^{[6
]}

Waldron, Gareth J. ^{[3
]}

Wang, Fen ^{[6
]}

Warmus, Joseph S. ^{[5
]}

机构：

[1] Pfizer Worldwide R&D UK, Worldwide Med Chem, Portway Bldg,Granta Pk, Cambridge CB21 6GS, England

[2] Pfizer Worldwide R&D UK, Pharmacokinet Dynam & Metab, Portway Bldg,Granta Pk, Cambridge CB21 6GS, England

[3] Pfizer Worldwide R&D UK, Portway Bldg,Granta Pk, Cambridge CB21 6GS, England

[4] Pfizer Worldwide R&D UK, Sandwich CT13 9NJ, Kent, England

[5] Pfizer Worldwide R&D, Groton Labs, Eastern Point Rd, Groton, CT 06340 USA

[6] Pfizer Worldwide R&D, La Jolla Labs, 10770 Sci Ctr Dr, San Diego, CA 92121 USA

[7] Peakdale Mol, Discovery Pk House,Ramsgate Rd, Sandwich CT13 9ND, Kent, England

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2018年 / 61卷 / 15期

关键词：

P-GLYCOPROTEIN; BINDING; TANEZUMAB; CNS; NEUROTROPHIN-3; PF-06273340; SOLUBILITY; EFFICACY; IMATINIB; PROTEIN;

D O I：

10.1021/acs.jmedchem.8b00633

中图分类号：

R914 [药物化学];

学科分类号：

100705 [微生物与生化药学];

摘要：

Hormones of the neurotrophin family, nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and neurotrophin 4 (NT4), are known to activate the family of Tropomyosin receptor kinases (TrkA, TrkB, and TrkC). Moreover, inhibition of the TrkA kinase pathway in pain has been clinically validated by the NGF antibody tanezumab, leading to significant interest in the development of small molecule inhibitors of TrkA. Furthermore, Trk inhibitors having an acceptable safety profile will require minimal brain availability. Herein, we discuss the discovery of two potent, selective, peripherally restricted, efficacious, and well-tolerated series of pan-Trk inhibitors which successfully delivered three candidate quality compounds 10b, 13b, and 19. All three compounds are predicted to possess low metabolic clearance in human that does not proceed via aldehyde oxidase-catalyzed reactions, thus addressing the potential clearance prediction liability associated with our current pan-Trk development candidate PF-06273340.

引用

页码：6779 / 6800

页数：22

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