- 6-Acylamino-2-[(ethylsulfonyl)oxy]-1H-isoindole-1,3-diones mechanism-based inhibitors of human leukocyte elastase and cathepsin G: Effect of chirality in the 6-acylamino substituent on inhibitory potency and selectivity
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Inhibition of human leukocyte elastase(HLE) by a series of 6-acylamino-2-[(ethylsulfonyl)oxy)]-1H-isoindole-1,3-diones was determined and compared to their inhibition of ChT, PPE, and Cat G. The best inhibitor of the series was 6-((1′S)-camphanyl)amino-2-[(ethylsulfonyl)oxy]-1H-isoindole-1,3-dione 5b, with a kobs/[I]=11,000M-1 s-1. This study revealed that HLE shows a preference for the S stereochemistry and tolerates hydrophobic substituents in the Sn′ binding sites. Molecular modeling of noncovalent HLE-inhibitor complexes was used as a tool to investigate our binding model. Buffer stability assays reveal that these compounds are susceptible to hydrolysis at physiological pH. Copyright
- Vagnoni, Lisa M.,Gronostaj, Michael,Kerrigan, John E.
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- Asymmetric synthesis and enantiospecificity of binding of 2-(1,2,3,4-tetrahydro-1-isoquinolyl)-ethanol derivatives to μ and κ receptors
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A number of 2-(1,2,3,4-tetrahydro-1-isoquinolyl)-ethanol derivatives 7a-e have been synthesized in diastereomerically and enantiomerically pure form and have been evaluated for their binding affinity at μ and κ opioid receptors. The amido ketones 5a-c and ent-5a-c, which were accessible by employing 3b and ent-3b for Asymmetric Electrophilic Amidoalkylation reactions, served as starting compounds. Upon reduction of 5a-c and ent-5a-c the amido alcohols l-6a-c, u-6a-c, ent-l-6a-c and ent-u-6a-c were obtained. Hydrolysis of these compounds yielded the secondary amino alcohols l-7a-c, u-7a-c, ent-l-7a-c and ent-u-7a-c and upon reductive methylation of l-7b-c, u-7b-c, ent-l-7b-c and ent-u-7b-c with CH2O and NaCNBH3 the tertiary amino alcohols l-7d-e, u-7d-e, ent-l-7d-e and ent-u-7d-e were obtained. The binding affinities of the final compounds l-7a-e, u-7a-e, ent-l-7a-e and ent-u-7a-e at both the μ and the κ receptor were strongly dependent on their stereochemistry. In each case isomers exhibited higher affinity at the μ than at the κ receptor. For the secondary amino alcohols 7a-c the affinity at the μ receptor followed the stereochemical order l-7 > ent-l-7 > ent-u-7 > u-7 whereas for the tertiary amino alcohols the order l-7 > u-7 > ent-l-7 > ent-u-7 was found. The stereoisomers l-7d and l-7e of the tertiary amino alcohols were found to be the most active compounds the latter exhibiting a K(i) value of 7.17 which is close to that of Morphine (K(i) 1.64). In an in vivo model, the Writhing Test, both compounds l-7d and l-7e displayed high analgetic activity.
- Wanner, Klaus Th.,Praschak, Ilona,Hoefner, Georg,Beer, Herbert
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- Preparation of (-)-(1S,4R)-Camphanoyl Chloride heptane-1-carbonyl Chloride, 4,7,7-Trimethyl-3-oxo, (1S)->
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A convenient three step procedure for the preparation of (-)-(1S,4R)-camphanoyl chloride, starting from (+)-camphoric acid (A) via (-)-bromocamphoric anhydride (B) and (-)-camphanic acid (C) is described.
- Kappes, Dag,Gerlach, Hans
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p. 581 - 587
(2007/10/02)
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