Improvement in oral bioavailability of 2,4-diaminopyrimidine c-Met inhibitors by incorporation of a 3-amidobenzazepin-2-one group

Milkiewicz, Karen L.; Aimone, Lisa D.; Albom, Mark S.; Angeles, Thelma S.; Chang, Hong Seong; Grobelny, Jennifer V.; Husten, Jean; LoSardo, Christine; Miknyoczki, Sheila; Murthy, S. N. Prasanna; Rolon-Steele, Damaris; Underiner, Ted L.; Weinberg, Linda R.; Worrell, Candace S.; Zeigler, Kelli S.; Dorsey, Bruce D.

doi:10.1016/j.bmc.2011.09.006

Cited by 13 publications

(11 citation statements)

References 31 publications

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“…Deprotection of 13i with TFA resulted in 13l . Further modification through acetylation of 13l to 13m resulted in complete loss of inhibitory activity. While a positively charged “tail” retained some inhibitory activity ( 13d and 13g ), the quaternary ammonium side chain of compound 13k , which was formed by alkylation with CH 3 I, is quite bulky and likely disrupts important binding interactions.…”

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confidence: 99%

Synthesis and Evaluation of Quinazolines as Inhibitors of the Bacterial Cell Division Protein FtsZ

Nepomuceno

Chan

Huynh

et al. 2015

ACS Med. Chem. Lett.

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The bacterial cell division protein FtsZ is one of many potential targets for the development of novel antibiotics. Recently, zantrin Z3 was shown to be a cross-species inhibitor of FtsZ; however, its specific interactions with the protein are still unknown. Herein we report the synthesis of analogues that contain a more tractable core structure and an analogue with single-digit micromolar inhibition of FtsZ's GTPase activity, which represents the most potent inhibitor of Escherichia coli FtsZ reported to date. In addition, the zantrin Z3 core has been converted to two potential photo-cross-linking reagents for proteomic studies that could shed light on the molecular interactions between FtsZ and molecules related to zantrin Z3.

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confidence: 99%

Synthesis and Evaluation of Quinazolines as Inhibitors of the Bacterial Cell Division Protein FtsZ

Nepomuceno

Chan

Huynh

et al. 2015

ACS Med. Chem. Lett.

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“…Parameter settings are summarized in Supplementary Tables S1 and S2. Each δ parameter was assigned a value consistent with a known drug half-life 31,[45][46][47][48][49] (Supplementary Table S2). Other parameters were assigned values that allow the model to reproduce the qualitative signaling behaviors of the AMPK-MTORC1-ULK1 triad characterized in the theoretical study of Szymańska et al 33 and to reproduce the timescale of autophagy induction and the range of regulation quantified experimentally in the study of Martin et al 34 .…”

Section: Model For Cellular Regulation Of Autophagy and The Effects O...mentioning

confidence: 99%

Prediction of Optimal Drug Schedules for Controlling Autophagy

Shirin¹,

Klickstein²,

Feng³

et al. 2018

Preprint

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The effects of molecularly targeted drug perturbations on cellular activities and fates are difficult to predict using intuition alone because of the complex behaviors of cellular regulatory networks. An approach to overcoming this problem is to develop mathematical models for predicting drug effects. Such an approach beckons for co-development of computational methods for extracting insights useful for guiding therapy selection and optimizing drug scheduling. Here, we present and evaluate a generalizable strategy for identifying drug dosing schedules that minimize the amount of drug needed to achieve sustained suppression or elevation of an important cellular activity/process, the recycling of cytoplasmic contents through (macro)autophagy. Therapeutic targeting of autophagy is currently being evaluated in diverse clinical trials but without the benefit of a control engineering perspective. Using a nonlinear ordinary differential equation (ODE) model that accounts for activating and inhibiting influences among protein and lipid kinases that regulate autophagy (MTORC1, ULK1, AMPK and VPS34) and methods guaranteed to find locally optimal control strategies, we find optimal drug dosing schedules (open-loop controllers) for each of six classes of drugs and drug pairs. Our approach is generalizable to designing monotherapy and multi therapy drug schedules that affect different cell signaling networks of interest.

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“…The 2,4-diarylaminopyrimidine (DAAP) scaffold has long been recognized as a classical kinase inhibitor motif. , Compounds 1 (NVP-TAE226) and 2 (NVP-TAE684) were among the earliest DAAP analogues (DAAPalogues) developed by Novartis showing high ALK inhibitory activities (Figure ). With compound 2 as a starting point, extensive work has been reported by Cephalon’s research team either by cyclizing the piperidinylaniline moiety (left ring) into a seven-membered bicyclic motif (benzocycloheptene, C1 nonsubstituted benzazepine, , benzoxazepine, or benzazepinone ,− as in compounds 3 and 4 ) or by replacing the aminobenzamide/sulfonylaniline (right ring) with a bicyclo[2.2.1]hept-5-ene motif , (as in compound 4 ). Interestingly, these new DAAPalogues displayed variant potencies against either c-Met or ALK.…”

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confidence: 99%

“…Interestingly, these new DAAPalogues displayed variant potencies against either c-Met or ALK. For example, compound 3 bearing a 3-amidobenzazepin-2-one component displayed an IC 50 value of 24 nM against c-Met kinase, while compound 4 bearing a 3-aminobicyclo[2.2.1]hept-5-ene-2-carboxylic acid amido fragment was found inactive against c-Met but exhibited high potency against ALK kinase.…”

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confidence: 99%

Novel 2,4-Diarylaminopyrimidine Analogues (DAAPalogues) Showing Potent c-Met/ALK Multikinase Inhibitory Activities

Liu

Xia

et al. 2014

ACS Med. Chem. Lett.

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By repurposing a typical dopamine D1/D5 receptor agonist motif, C1-substituted-N3-benzazepine or benzazecine, into the classical RTK inhibitor 2,4-diaminopyrimidine skeleton, a series of new 2,4-diarylaminopyrimidine analogues (DAAPalogues) were developed. Compounds 7 and 8a were identified possessing high potency against both c-Met and ALK kinases. Compound 8a displayed appreciable antitumor efficacy at the dose of 1 mg/kg in the ALK-driven BF3/EML4-ALK xenograft mice model.

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Improvement in oral bioavailability of 2,4-diaminopyrimidine c-Met inhibitors by incorporation of a 3-amidobenzazepin-2-one group

Cited by 13 publications

References 31 publications

Synthesis and Evaluation of Quinazolines as Inhibitors of the Bacterial Cell Division Protein FtsZ

Synthesis and Evaluation of Quinazolines as Inhibitors of the Bacterial Cell Division Protein FtsZ

Prediction of Optimal Drug Schedules for Controlling Autophagy

Novel 2,4-Diarylaminopyrimidine Analogues (DAAPalogues) Showing Potent c-Met/ALK Multikinase Inhibitory Activities

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