Based on the scaffold of the pharmacologically selective thyromimetic 2b, structurally a close analog to KB-141 (2a), a number of novel N-acylated-alpha-amino acid derivatives were synthesized and tested in a TR radioligand binding assay as well as in a reporter cell assay. On the basis of TRbeta(1)-isoform selectivity and affinity, as well as affinity to the reporter cell assay, 3d was selected for further studies in the cholesterol-fed rat model. In this model 3d revealed an improved therapeutic window between cholesterol and TSH lowering but decreased margins versus tachycardia compared with 2a.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1016/j.bmcl.2007.05.049 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Formation and hydrolysis of amide bonds by lipase A from Candida antarctica; exceptional features.
Org Biomol Chem
February 2010
Institute of Biomedicine, Pharmacology, Drug Development and Therapeutics/Laboratory of Synthetic Drug Chemistry and Department of Chemistry, University of Turku, Lemminkäisenkatu 5 C, FIN-20520, Turku, Finland.
Various commercial lyophilized and immobilized preparations of lipase A from Candida antarctica (CAL-A) were studied for their ability to catalyze the hydrolysis of amide bonds in N-acylated alpha-amino acids, 3-butanamidobutanoic acid (beta-amino acid) and its ethyl ester. The activity toward amide bonds is highly untypical of lipases, despite the close mechanistic analogy to amidases which normally catalyze the corresponding reactions. Most CAL-A preparations cleaved amide bonds of various substrates with high enantioselectivity, although high variations in substrate selectivity and catalytic rates were detected.
View Article and Find Full Text PDFThyroid receptor ligands. Part 8: Thyromimetics derived from N-acylated-alpha-amino acid derivatives displaying modulated pharmacological selectivity compared with KB-141.
Bioorg Med Chem Lett
August 2007
Karo Bio AB, Novum, Huddinge S-141 57, Sweden.
Based on the scaffold of the pharmacologically selective thyromimetic 2b, structurally a close analog to KB-141 (2a), a number of novel N-acylated-alpha-amino acid derivatives were synthesized and tested in a TR radioligand binding assay as well as in a reporter cell assay. On the basis of TRbeta(1)-isoform selectivity and affinity, as well as affinity to the reporter cell assay, 3d was selected for further studies in the cholesterol-fed rat model. In this model 3d revealed an improved therapeutic window between cholesterol and TSH lowering but decreased margins versus tachycardia compared with 2a.
View Article and Find Full Text PDFSynthesis of a polymer-bound galactosylamine and its application as an immobilized chiral auxiliary in stereoselective syntheses of piperidine and amino acid derivatives.
Chemistry
September 2004
Institut für Organische Chemie der Universität Mainz, Duesbergweg 10-14, 55128 Mainz, Germany.
A 2,3,4-tri-O-pivaloylated beta-D-galactopyranosyl azide bearing a hydroxy-functionalized spacer unit at the C-6 position of the galactose was synthesized and immobilized on the solid phase by using a polymer-bound chlorosilane. The azide was reduced to the corresponding galactopyranosylamine, which served as a versatile chiral auxiliary in highly diastereoselective Ugi four-component condensation reactions at ambient temperature. Fluoride-induced cleavage from the polymeric support furnished N-glycosylated N-acylated alpha-amino acid amides.
View Article and Find Full Text PDFEnantioselective hydrolysis of N-acylated alpha-amino esters at a biphasic interface: tandem reaction kinetic resolution using a chiral complexing agent.
Org Lett
September 2002
School of Chemical Sciences, University of Illinois at Urbana-Champaign, 61801, USA.
[reaction: see text] Highly enantioselective hydrolytic kinetic resolutions of esters derived from N-acylated alpha-amino acids proceed rapidly at hydrocarbon/water interfaces in the presence of a proline-derived chiral selector. When performed in tandem with an enantioselective biphasic esterification reaction, esters of 100% enantiomeric excess are obtained
View Article and Find Full Text PDFStereoselective synthesis of 2-aminocyclobutanols via photocyclization of alpha-amido alkylaryl ketones: mechanistic implications for the Norrish/Yang reaction.
J Am Chem Soc
January 2002
Institute of Organic Chemistry, Greinstrasse 4, D-50939 Köln, Germany.
A series of chiral N-acylated alpha-amino p-methylbutyrophenone derivatives 1a-1h was synthesized from alpha-amino acids via a three-step procedure. These substrates were photolyzed in benzene and gave Norrish II and Norrish I cleavage products as well as the N-acylated 2-aminocyclobutanols that derive from gamma-hydrogen abstraction and 1,4-triplet biradical combination (Yang cyclization). The products were formed with characteristic Yang/cleavage ratios.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!