Synthesis and cathepsin D inhibition of peptide-hydroxyethyl amine isosteres with cyclic tertiary amines |
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Authors: | Rose M McConnell Walter E Godwin Amy Stefan Crystal Newton Nikki Myers and Susan E Hatfield |
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Institution: | (1) School of Mathematical & Natural Sciences, University of Arkansas at Monticello, 71656 Monticello, AR;(2) Department of Chemistry, Texas A & M University, College Station, TX |
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Abstract: | Summary Cathepsin D, a lysosomal aspartic protease, has been suggested to play a role in the metastatic potential of several types
of cancer. A high activated cathepsin D level in breast tumor tissue has been associated with an increased incidence of relapse
and metastasis. High levels of active cathepsin D have also been found in colon cancer, prostate cancer, uterine cancer and
ovarian cancer. Hydroxyethyl isosteres with cyclic tertiary amine have proven to be clinically useful as inhibitors of aspartyl
proteases similar to cathepsin D in activity, such as the HIV-1 aspartyl protease. The design and the synthesis of (hydroxyethyl)amine
isostere inhibitors with cyclic tertiary amines is described. The IC50 and Ki(app) values for the six cathepsin D inhibitors and pepstatin are reported. Compounds7b,3(S)-Acetyl-L-valyl-L-phenylalanylamino]-4-phenyl-1-N-piperidine-2(S)-butanol, and7c, 3(S)-Acetyl-L-leucyl-L-phenylalanylamino]-4-phenyl-1-N-piperidine-2(S)-butanol, showed the most potent inhibition of cathepsin
D hydrolysis of hemoglobin with IC50 values of 3.5 nM and 4.5 nM, respectively. |
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Keywords: | cathepsin D inhibitors hydroxyethylamine isosteres |
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