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Design and synthesis of brain penetrant selective JNK inhibitors with improved pharmacokinetic properties for the prevention of neurodegeneration.

Bowers, Simeon; Truong, Anh P; Jeffrey Neitz, R; Hom, Roy K; Sealy, Jennifer M; Probst, Gary D; Quincy, David; Peterson, Brian; Chan, Wayman; Galemmo, Robert A; Konradi, Andrei W; Sham, Hing L; Tóth, Gergely; Pan, Hu; Lin, May; Yao, Nanhua; Artis, Dean R; Zhang, Heather; Chen, Linda; Dryer, Mark; Samant, Bhushan; Zmolek, Wes; Wong, Karina; Lorentzen, Colin; Goldbach, Erich; Tonn, George; Quinn, Kevin P; Sauer, John-Michael; Wright, Sarah; Powell, Kyle; Ruslim, Lany; Ren, Zhao; Bard, Frédérique; Yednock, Ted A; Griswold-Prenner, Irene.

Bioorg Med Chem Lett ; 21(18): 5521-7, 2011 Sep 15.

Article in English | MEDLINE | ID: mdl-21813278

ABSTRACT

The SAR of a series of brain penetrant, trisubstituted thiophene based JNK inhibitors with improved pharmacokinetic properties is described. These compounds were designed based on information derived from metabolite identification studies which led to compounds such as 42 with lower clearance, greater brain exposure and longer half life compared to earlier analogs.

Subject(s)

Brain/metabolism , Drug Design , Nerve Degeneration/prevention & control , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Thiophenes/pharmacology , Thiophenes/pharmacokinetics , Animals , Chemistry Techniques, Synthetic , Crystallography, X-Ray , Dose-Response Relationship, Drug , Half-Life , JNK Mitogen-Activated Protein Kinases/antagonists & inhibitors , JNK Mitogen-Activated Protein Kinases/metabolism , Mice , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacokinetics , Stereoisomerism , Structure-Activity Relationship , Thiophenes/chemical synthesis , Thiophenes/chemistry

ABSTRACT

Subject(s)

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