Bioorganic & medicinal chemistry letters
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Bioorg. Med. Chem. Lett. · Jun 2010
2' biaryl amides as novel and subtype selective M1 agonists. Part II: Further optimization and profiling.
Further optimization of the biaryl amide series via extensively exploring structure-activity relationships resulted in potent and subtype selective M(1) agonists exemplified by compounds 9a and 9j with good rat PK properties including CNS penetration. Synthesis, structure-activity relationships, subtype selectivity for M(1) over M(2-5), and DMPK properties of these novel compounds are described.
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Bioorg. Med. Chem. Lett. · May 2010
Inhibition of gamma-secretase by the CK1 inhibitor IC261 does not depend on CK1delta.
CK1 and gamma-secretase are interesting targets for therapeutic intervention in the treatment of cancer and Alzheimer's disease. The CK1 inhibitor IC261 was reported to inhibit gamma-secretase activity. ⋯ The most active compounds were investigated on CK1delta activity. These findings exclude a direct influence of CK1delta on gamma-secretase, because any change in the substitution pattern of IC261 diminished CK1 inhibition, whereas gamma-secretase inhibition is still exerted by several analogues.
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Bioorg. Med. Chem. Lett. · Feb 2010
Design, synthesis, and biological evaluation of potent thiosemicarbazone based cathepsin L inhibitors.
A small library of 36 functionalized benzophenone thiosemicarbazone analogs has been prepared by chemical synthesis and evaluated for their ability to inhibit the cysteine proteases cathepsin L and cathepsin B. Inhibitors of cathepsins L and B have the potential to limit or arrest cancer metastasis. ⋯ These six analogs are selective for their inhibition of cathepsin L versus cathepsin B (IC50>10,000 nM). The most active analog in the series, 3-bromophenyl-2'-fluorophenyl thiosemicarbazone 1, also efficiently inhibits cell invasion of the DU-145 human prostate cancer cell line.
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Bioorg. Med. Chem. Lett. · Feb 2010
Comparative StudySynthesis and biological evaluation of new potential inhibitors of N-acylethanolamine hydrolyzing acid amidase.
N-Acylethanolamines, including N-palmitoyl-ethanolamine (PEA), are hydrolyzed to the corresponding fatty acids and ethanolamine by fatty acid amide hydrolase (FAAH). Recently, N-acylethanolamine-hydrolyzing acid amidase (NAAA) was identified as being able to specifically hydrolyze PEA. ⋯ Cyclopentylhexadecanoate (13) exhibited the highest inhibitory activity on NAAA (IC(50)=10.0 microM), without inhibiting FAAH up to 50 microM. Compound 13 may become a useful template to design new NAAA inhibitors.
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Bioorg. Med. Chem. Lett. · Jan 2010
Chemical lead optimization of a pan G(q) mAChR M(1), M(3), M(5) positive allosteric modulator (PAM) lead. Part I: Development of the first highly selective M(5) PAM.
This Letter describes a chemical lead optimization campaign directed at VU0238429, the first M(5)-preferring positive allosteric modulator (PAM), discovered through analog work around VU0119498, a pan G(q) mAChR M(1), M(3), M(5) PAM. An iterative library synthesis approach delivered the first selective M(5) PAM (no activity at M(1)-M(4) @ 30microM), and an important tool compound to study the role of M(5) in the CNS.