- Multi-kilo delivery of AMG 925 featuring a buchwald-hartwig amination and processing with insoluble synthetic intermediates
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The development of a synthetic route to manufacture the drug candidate AMG 925 on kilogram scale is reported herein. The hydrochloride salt of AMG 925 was prepared in 23% overall yield over eight steps from commercially available raw materials, and more than 8 kg of the target molecule were delivered. The synthetic route features a Buchwald-Hartwig amination using BrettPhos as ligand and conducted to afford 12 kg of product in a single batch. In addition, this work highlights the challenges associated with the use of poorly soluble process intermediates in the manufacture of active pharmaceutical ingredients. Creative solutions had to be devised to conduct seemingly routine activities such as salt removal, pH adjustment, and heavy metal scavenging due to the low solubility of the process intermediates. Finally, a slurry-to-slurry amidation protocol was optimized to allow for successful scale-up.
- Affouard, Caroline,Crockett, Richard D.,Diker, Khalid,Farrell, Robert P.,Gorins, Gilles,Huckins, John R.,Caille, Seb
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p. 476 - 485
(2015/04/14)
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- Discovery of AMG 925, a FLT3 and CDK4 dual kinase inhibitor with preferential affinity for the activated state of FLT3
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We describe the structural optimization of a lead compound 1 that exhibits dual inhibitory activities against FLT3 and CDK4. A series of pyrido[4′,3′:4,5]pyrrolo[2,3-d]pyrimidine derivatives was synthesized, and SAR analysis, using cell-based assays, led to the discovery of 28 (AMG 925), a potent and orally bioavailable dual inhibitor of CDK4 and FLT3, including many FLT3 mutants reported to date. Compound 28 inhibits the proliferation of a panel of human tumor cell lines including Colo205 (Rb +) and U937 (FLT3WT) and induced cell death in MOLM13 (FLT3ITD) and even in MOLM13 (FLT3ITD, D835Y), which exhibits resistance to a number of FLT3 inhibitors currently under clinical development. At well-tolerated doses, compound 28 leads to significant growth inhibition of MOLM13 xenografts in nude mice, and the activity correlates with inhibition of STAT5 and Rb phosphorylation.
- Li, Zhihong,Wang, Xianghong,Eksterowicz, John,Gribble, Michael W.,Alba, Grace Q.,Ayres, Merrill,Carlson, Timothy J.,Chen, Ada,Chen, Xiaoqi,Cho, Robert,Connors, Richard V.,Degraffenreid, Michael,Deignan, Jeffrey T.,Duquette, Jason,Fan, Pingchen,Fisher, Benjamin,Fu, Jiasheng,Huard, Justin N.,Kaizerman, Jacob,Keegan, Kathleen S.,Li, Cong,Li, Kexue,Li, Yunxiao,Liang, Lingming,Liu, Wen,Lively, Sarah E.,Lo, Mei-Chu,Ma, Ji,McMinn, Dustin L.,Mihalic, Jeffrey T.,Modi, Kriti,Ngo, Rachel,Pattabiraman, Kanaka,Piper, Derek E.,Queva, Christophe,Ragains, Mark L.,Suchomel, Julia,Thibault, Steve,Walker, Nigel,Wang, Xiaodong,Wang, Zhulun,Wanska, Malgorzata,Wehn, Paul M.,Weidner, Margaret F.,Zhang, Alex J.,Zhao, Xiaoning,Kamb, Alexander,Wickramasinghe, Dineli,Dai, Kang,McGee, Lawrence R.,Medina, Julio C.
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p. 3430 - 3449
(2014/05/20)
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- FUSED TRICYCLIC DUAL INHIBITORS OF CDK 4/6 AND FLT3
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Compounds of Formula I are useful inhibitors of CDK 4, CDK6, and FLT3. Such compounds are useful in treating cancer and various other disease conditions. Compounds of Formula I have the following structure: where R1 is a group of Formula IA, Formula IB, Formula IC, or Formula ID and the definitions of the other variables are provided herein.
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