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1.
Bioorg Med Chem ; 15(3): 1311-22, 2007 Feb 01.
Article in English | MEDLINE | ID: mdl-17127070

ABSTRACT

Peptidomimetic compounds possessing a caprolactam ring constraint were prepared and evaluated as interleukin-1beta converting enzyme (ICE) inhibitors. The caprolactam ring was used to constrain the P3 region of our inhibitors. This strategy proved to be effective for the synthesis of ICE inhibitors, maintaining key hydrogen bond interactions with the enzyme and invoking a preferred conformation for binding. Several compounds exhibited IC(50) values less than 10nM in a caspase-1 enzyme assay and less than 100nM in a THP-1 whole cell assay measuring IL-1beta production. Two compounds, 13c and 13j, were found to have good oral bioavailability (>50%) in rats when administered as prodrugs.


Subject(s)
Caprolactam/chemical synthesis , Caspase Inhibitors , Enzyme Inhibitors/pharmacology , Serpins/chemical synthesis , Viral Proteins/chemical synthesis , Animals , Biological Availability , Caprolactam/chemistry , Caprolactam/pharmacology , Crystallography, X-Ray , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Hydrogen Bonding , Interleukin-1beta/metabolism , Male , Models, Molecular , Molecular Conformation , Molecular Structure , Rats , Rats, Sprague-Dawley , Serpins/pharmacology , Structure-Activity Relationship , Viral Proteins/pharmacology
2.
Bioorg Med Chem ; 14(23): 7880-92, 2006 Dec 01.
Article in English | MEDLINE | ID: mdl-16908171

ABSTRACT

An 8,5-fused bicyclic peptidomimetic ring system generated by a stereoselective ring metathesis reaction was elaborated into potent inhibitors of interleukin-1beta converting enzyme (ICE, caspase-1). Multiple compounds were found that exhibited ICE IC50 values < 10 nM and were selective over caspase-3 and caspase-8. These active analogs generally possessed good activity (IC50 values < 100 nM) in a whole cell assay measuring IL-1beta production. Pharmacokinetic analysis of the ethyl acetal prodrug form of a selected active lead revealed a compound with a reasonable plasma half-life (1.1 h) and good oral bioavailability (30%).


Subject(s)
Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Caspase Inhibitors , Peptides, Cyclic/pharmacology , Animals , Biological Availability , Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/pharmacology , Half-Life , Inhibitory Concentration 50 , Molecular Mimicry , Peptides, Cyclic/chemical synthesis , Prodrugs/pharmacokinetics , Structure-Activity Relationship , Substrate Specificity
3.
Bioorg Med Chem Lett ; 16(18): 4728-32, 2006 Sep 15.
Article in English | MEDLINE | ID: mdl-16870441

ABSTRACT

A series of monocyclic thiazepine inhibitors of interleukin-1beta converting enzyme (ICE) were synthesized in eight steps from commercially available intermediates. In vitro biological evaluation showed the thiazepines to be moderately potent ICE inhibitors, with the most active compound exhibiting an IC50 value of 30 nM in an enzyme inhibition assay. Compounds of this class possessed good selectivity against the related enzymes caspase-3 and caspase-8.


Subject(s)
Caspase Inhibitors , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Thiazepines/chemical synthesis , Thiazepines/pharmacology , Caspase 1/metabolism , Crystallography, X-Ray , Enzyme Inhibitors/chemistry , Inhibitory Concentration 50 , Models, Molecular , Molecular Structure , Structure-Activity Relationship , Thiazepines/chemistry
4.
Bioorg Med Chem Lett ; 16(16): 4233-6, 2006 Aug 15.
Article in English | MEDLINE | ID: mdl-16782334

ABSTRACT

Novel 1-(2-acylhydrazinocarbonyl)cycloalkyl carboxamides were designed as peptidomimetic inhibitors of interleukin-1beta converting enzyme (ICE). A short synthesis was developed and moderately potent ICE inhibitors were identified (IC(50) values <100 nM). Most of the synthesized examples were selective for ICE versus the related cysteine proteases caspase-3 and caspase-8, although several dual-acting inhibitors of ICE and caspase-8 were identified. Several of the more potent ICE inhibitors were also shown to inhibit IL-1beta production in a whole cell assay (IC(50) < 500 nM).


Subject(s)
Amides/chemical synthesis , Amides/pharmacology , Aminoimidazole Carboxamide/chemical synthesis , Caspase Inhibitors , Hydrazines/chemical synthesis , Hydrazines/pharmacology , Aminoimidazole Carboxamide/analogs & derivatives , Caspase 8 , Chemistry, Pharmaceutical/methods , Cysteine Endopeptidases/metabolism , Drug Industry/methods , Drug Screening Assays, Antitumor , Enzyme Inhibitors/pharmacology , Humans , Inhibitory Concentration 50 , Models, Chemical
5.
Bioorg Med Chem Lett ; 15(24): 5434-8, 2005 Dec 15.
Article in English | MEDLINE | ID: mdl-16216507

ABSTRACT

Two novel 8,6-fused bicyclic peptidomimetic ring systems were synthesized utilizing olefin metathesis as the key reaction for the formation of the eight-membered ring. Both peptidomimetic scaffolds were further elaborated into potent ICE inhibitors, with numerous compounds exhibiting caspase-1 IC(50)s less than 10nM.


Subject(s)
Biomimetics , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Caspase Inhibitors , Enzyme Inhibitors/pharmacology , Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Humans , Indicators and Reagents , Models, Molecular , Molecular Conformation
6.
Bioorg Med Chem Lett ; 15(19): 4291-4, 2005 Oct 01.
Article in English | MEDLINE | ID: mdl-16046125

ABSTRACT

A novel diazocan containing dipeptide mimetic was synthesized via reductive N-N bond cleavage of a pyrazolidino-pyrazolidine using Raney-Ni and evaluated as an ICE inhibitor. This versatile 8-membered ring containing scaffold possesses an N-5 ring nitrogen that was used to explore structure-activity relationships in a cell-based assay measuring inhibition of interleukin-1beta.


Subject(s)
Dipeptides/chemical synthesis , Interleukin-1/antagonists & inhibitors , Peptides, Cyclic/chemical synthesis , Caspase Inhibitors , Dipeptides/chemistry , Dipeptides/pharmacology , Drug Evaluation, Preclinical , Inhibitory Concentration 50 , Interleukin-1/biosynthesis , Molecular Conformation , Molecular Mimicry , Peptides, Cyclic/chemistry , Peptides, Cyclic/pharmacology , Pyrazoles/chemistry , Structure-Activity Relationship
7.
Bioorg Med Chem Lett ; 15(19): 4322-6, 2005 Oct 01.
Article in English | MEDLINE | ID: mdl-16046129

ABSTRACT

The application of a tricyclic pyrrolopyrimidinone scaffold for the synthesis of peptidomimetic inhibitors of interleukin-1beta-converting enzyme (ICE) is reported. The synthesis of the tricyclic scaffold and conversion of it to a variety of target ICE inhibitors were accomplished in 4-5 steps. In vitro biological evaluation of the tricyclic pyrrolopyrimidinones revealed fair to good ICE inhibitors, with the most active compound exhibiting an IC50 of 14 nM in a caspase-1 enzyme binding assay.


Subject(s)
Caspase Inhibitors , Dipeptides/chemical synthesis , Pyrimidinones/chemical synthesis , Dipeptides/pharmacology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Heterocyclic Compounds, 3-Ring/chemical synthesis , Heterocyclic Compounds, 3-Ring/pharmacology , Humans , Immunologic Factors/chemical synthesis , Immunologic Factors/pharmacology , Inhibitory Concentration 50 , Molecular Mimicry , Monocytes , Pyrimidinones/pharmacology , Pyrroles/chemical synthesis , Pyrroles/pharmacology , Structure-Activity Relationship
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