| Autor: |
Riether D; Medicinal Chemistry Department, Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Rd./PO Box 368, Ridgefield, CT 06877, USA., Zindell R, Kowalski JA, Cook BN, Bentzien J, Lombaert SD, Thomson D, Kugler SZ Jr, Skow D, Martin LS, Raymond EL, Khine HH, O'Shea K, Woska JR Jr, Jeanfavre D, Sellati R, Ralph KL, Ahlberg J, Labissiere G, Kashem MA, Pullen SS, Takahashi H |
| Jazyk: |
angličtina |
| Zdroj: |
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2009 Mar 15; Vol. 19 (6), pp. 1588-91. Date of Electronic Publication: 2009 Feb 08. |
| DOI: |
10.1016/j.bmcl.2009.02.012 |
| Abstrakt: |
Benzamide 1 demonstrated good potency as a selective ITK inhibitor, however the amide moiety was found to be hydrolytically labile in vivo, resulting in low oral exposure and the generation of mutagenic aromatic amine metabolites. Replacing the benzamide with a benzylamine linker not only addressed the toxicity issue, but also improved the cellular and functional potency as well as the drug-like properties. SAR studies around the benzylamines and the identification of 10n and 10o as excellent tools for proof-of-concept studies are described. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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