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DOI 10.1021/jm5013598

Медицинская библиотека · Journal of medicinal chemistry · 2015

Lead optimization toward proof-of-concept tools for Huntington's disease within a 4-(1H-pyrazol-4-yl)pyrimidine class of pan-JNK inhibitors.

Wityak John, McGee Kevin F, Conlon Michael P, Song Ren Hua, Duffy Bryan C, Clayton Brent, Lynch Michael, Wang Gwen, Freeman Emily, Haber James, Kitchen Douglas B, Manning David D, Ismail Jiffry, Khmelnitsky Yuri, Michels Peter, Webster Jeff, Irigoyen Macarena, Luche Michele, Hultman Monica, Bai Mei, Kuok IokTeng D, Newell Ryan, Lamers Marieke, Leonard Philip, Yates Dawn, Matthews Kim, Ongeri Lynette, Clifton Steve, Mead Tania, Deupree Susan, Wheelan Pat, Lyons Kathy, Wilson Claire, Kiselyov Alex, Toledo-Sherman Leticia, Beconi Maria, Muñoz-Sanjuan Ignacio, Bard Jonathan, Dominguez Celia

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Аннотация

Through medicinal chemistry lead optimization studies focused on calculated properties and guided by X-ray crystallography and computational modeling, potent pan-JNK inhibitors were identified that showed submicromolar activity in a cellular assay. Using in vitro ADME profiling data, 9t was identified as possessing favorable permeability and a low potential for efflux, but it was rapidly cleared in liver microsomal incubations. In a mouse pharmacokinetics study, compound 9t was brain-penetrant after oral dosing, but exposure was limited by high plasma clearance. Brain exposure at a level expected to support modulation of a pharmacodynamic marker in mouse was achieved when the compound was coadministered with the pan-cytochrome P450 inhibitor 1-aminobenzotriazole.

Для цитирования: Wityak John, McGee Kevin F, Conlon Michael P, Song Ren Hua, Duffy Bryan C, Clayton Brent, Lynch Michael, Wang Gwen, Freeman Emily, Haber James, Kitchen Douglas B, Manning David D, Ismail Jiffry, Khmelnitsky Yuri, Michels Peter, Webster Jeff, Irigoyen Macarena, Luche Michele, Hultman Monica, Bai Mei, Kuok IokTeng D, Newell Ryan, Lamers Marieke, Leonard Philip, Yates Dawn, Matthews Kim, Ongeri Lynette, Clifton Steve, Mead Tania, Deupree Susan, Wheelan Pat, Lyons Kathy, Wilson Claire, Kiselyov Alex, Toledo-Sherman Leticia, Beconi Maria, Muñoz-Sanjuan Ignacio, Bard Jonathan, Dominguez Celia. Lead optimization toward proof-of-concept tools for Huntington's disease within a 4-(1H-pyrazol-4-yl)pyrimidine class of pan-JNK inhibitors.. Journal of medicinal chemistry. 2015. DOI: 10.1021/jm5013598.

Предметные рубрики MeSH

AnimalsBlood-Brain BarrierChemistry Techniques, SyntheticCrystallography, X-RayCytochrome P-450 Enzyme InhibitorsDisease Models, AnimalDogsDrug Evaluation, PreclinicalHalf-LifeHumansHuntington DiseaseInhibitory Concentration 50Madin Darby Canine Kidney CellsMiceMicrosomes, LiverMitogen-Activated Protein Kinase 10Molecular StructureProtein Kinase InhibitorsPyrazolesPyrimidinesStructure-Activity Relationship
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