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1.
Bioorg Med Chem Lett ; 20(22): 6581-6, 2010 Nov 15.
Article in English | MEDLINE | ID: mdl-20875739

ABSTRACT

Starting from a tripeptide screening hit, a series of dipeptide inhibitors of the proteasome with Thr as the P3 residue has been optimized with the aid of crystal structures in complex with the ß-5/6 active site of y20S. Derivative 25, (ß5 IC(50)=7.4 nM) inhibits only the chymotryptic activity of the proteasome, shows cellular activity against targets in the UPS, and inhibits proliferation.


Subject(s)
Chymotrypsin/antagonists & inhibitors , Dipeptides/chemistry , Proteasome Endopeptidase Complex/metabolism , Threonine/chemistry , Humans , Models, Molecular
2.
Biochem J ; 430(3): 461-76, 2010 Sep 15.
Article in English | MEDLINE | ID: mdl-20632995

ABSTRACT

The mammalian 26S proteasome is a 2500 kDa multi-catalytic complex involved in intracellular protein degradation. We describe the synthesis and properties of a novel series of non-covalent di-peptide inhibitors of the proteasome based [corrected] on a capped tri-peptide that was first identified by high-throughput screening of a library of approx. 350000 compounds for inhibitors of the ubiquitin-proteasome system in cells. We show that these compounds are entirely selective for the beta5 (chymotrypsin-like) site over the beta1 (caspase-like) and beta2 (trypsin-like) sites of the 20S core particle of the proteasome, and over a panel of less closely related proteases. Compound optimization, guided by X-ray crystallography of the liganded 20S core particle, confirmed their non-covalent binding mode and provided a structural basis for their enhanced in vitro and cellular potencies. We demonstrate that such compounds show low nanomolar IC50 values for the human 20S beta5 site in vitro, and that pharmacological inhibition of this site in cells is sufficient to potently inhibit the degradation of a tetra-ubiquitin-luciferase reporter, activation of NFkappaB (nuclear factor kappaB) in response to TNF-alpha (tumour necrosis factor-alpha) and the proliferation of cancer cells. Finally, we identified capped di-peptides that show differential selectivity for the beta5 site of the constitutively expressed proteasome and immunoproteasome in vitro and in B-cell lymphomas. Collectively, these studies describe the synthesis, activity and binding mode of a new series of non-covalent proteasome inhibitors with unprecedented potency and selectivity for the beta5 site, and which can discriminate between the constitutive proteasome and immunoproteasome in vitro and in cells.


Subject(s)
Oligopeptides/pharmacology , Protease Inhibitors/pharmacology , Proteasome Inhibitors , Amino Acid Sequence , Binding Sites , Boronic Acids/pharmacology , Bortezomib , Cell Line , Cell Line, Tumor , Cell Proliferation/drug effects , Crystallography, X-Ray , HCT116 Cells , HT29 Cells , Humans , Kinetics , Luciferases/genetics , Luciferases/metabolism , Models, Molecular , Molecular Sequence Data , Molecular Structure , NF-kappa B/genetics , NF-kappa B/metabolism , Oligopeptides/chemistry , Oligopeptides/metabolism , Protease Inhibitors/chemistry , Protease Inhibitors/metabolism , Proteasome Endopeptidase Complex/genetics , Proteasome Endopeptidase Complex/metabolism , Protein Binding , Protein Structure, Tertiary , Protein Subunits/antagonists & inhibitors , Protein Subunits/genetics , Protein Subunits/metabolism , Pyrazines/pharmacology , RNA Interference , Sequence Homology, Amino Acid , Ubiquitin/genetics , Ubiquitin/metabolism
3.
J Med Chem ; 50(3): 566-84, 2007 Feb 08.
Article in English | MEDLINE | ID: mdl-17266208

ABSTRACT

The design, synthesis, and structure-activity relationship development of naphthalene-derived human CCR8 antagonists is described. In vitro binding assay results of these investigations are reported, critical interactions of the antagonists with CCR8 are defined, and preliminary physicochemical and pharmacokinetic data for the naphthalene scaffold are presented.


Subject(s)
Naphthalenes/chemical synthesis , Receptors, Chemokine/antagonists & inhibitors , Sulfonamides/chemical synthesis , Administration, Oral , Animals , Biological Availability , Biological Transport , Calcium/metabolism , Cell Line , Cricetinae , Cricetulus , Drug Design , Humans , Naphthalenes/pharmacokinetics , Naphthalenes/pharmacology , Rats , Receptors, CCR8 , Solubility , Stereoisomerism , Structure-Activity Relationship , Sulfonamides/pharmacokinetics , Sulfonamides/pharmacology
4.
J Med Chem ; 48(26): 8182-93, 2005 Dec 29.
Article in English | MEDLINE | ID: mdl-16366600

ABSTRACT

N-Substituted cis-4a-(3-hydroxyphenyl)-8a-methyloctahydroisoquinolines (6a-g) were designed and synthesized as conformationally constrained analogues of the trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine (4) class of opioid receptor pure antagonists. The methyloctahydroisoquinolines 6a-g can exist in conformations where the 3-hydroxyphenyl substituent is either axial or equatorial, similar to the (3-hydroxyphenyl)piperidines 4. The 3-hydroxyphenyl equatorial conformation is responsible for the antagonist activity observed in the (3-hydroxyphenyl)piperidine antagonists. Single-crystal X-ray analysis of 6a shows that the 3-hydroxyphenyl equatorial conformation is favored in the solid state. Molecular modeling studies also suggest that the equatorial conformation has lower potential energy relative to that of the axial conformation. Evaluation of 6a-g in the [(35)S]GTP-gamma-S in vitro functional assay showed that they were opioid receptor pure antagonists. N-[4a-(3-Hydroxyphenyl)-8a-methyl-2-(3-phenylpropyl)octahydroisoquinoline-6-yl]-3-(piperidin-1-yl)propionamide (6d) with a K(e) of 0.27 nM at the kappa opioid receptor with 154- and 46-fold selectivity relative to those of the micro and delta receptors, respectively, possessed the best combination of kappa potency and selectivity.


Subject(s)
Isoquinolines/pharmacology , Narcotic Antagonists , Animals , Benzeneacetamides/pharmacology , CHO Cells , Cricetinae , Enkephalin, Ala(2)-MePhe(4)-Gly(5)-/pharmacology , Enkephalin, D-Penicillamine (2,5)-/pharmacology , Guanosine 5'-O-(3-Thiotriphosphate)/antagonists & inhibitors , Guanosine 5'-O-(3-Thiotriphosphate)/metabolism , Humans , Isoquinolines/chemical synthesis , Models, Molecular , Molecular Conformation , Pyrrolidines/pharmacology , Receptors, Opioid/metabolism , Receptors, Opioid, delta/antagonists & inhibitors , Receptors, Opioid, kappa/antagonists & inhibitors , Receptors, Opioid, kappa/metabolism , Receptors, Opioid, mu/antagonists & inhibitors
5.
J Med Chem ; 45(16): 3524-30, 2002 Aug 01.
Article in English | MEDLINE | ID: mdl-12139463

ABSTRACT

A library of compounds biased toward opioid receptor antagonist activity was prepared by incorporating N-phenylpropyl-4beta-methyl-5-(3-hydroxyphenyl)morphans as the core scaffold using simultaneous solution phase synthetic methodology. From this library, N-phenylpropyl-4beta-methyl-5-(3-hydroxyphenyl)-7alpha-[3-(1-piperidinyl)propanamido]morphan [(-)-3b] was identified as the first potent and selective kappa opioid receptor antagonist from the 5-phenylmorphan class of opioids.


Subject(s)
Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Morphinans/chemical synthesis , Receptors, Opioid, kappa/antagonists & inhibitors , Animals , Brain/metabolism , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , CHO Cells , Combinatorial Chemistry Techniques , Cricetinae , Guinea Pigs , Humans , In Vitro Techniques , Ligands , Morphinans/chemistry , Morphinans/pharmacology , Radioligand Assay , Rats , Stereoisomerism , Structure-Activity Relationship
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