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1.
ACS Omega ; 6(29): 18635-18650, 2021 Jul 27.
Article in English | MEDLINE | ID: mdl-34337203

ABSTRACT

Here, we described the design, by fragment merging and multiparameter optimization, of selective MMP-13 inhibitors that display an appropriate balance of potency and physicochemical properties to qualify as tool compounds suitable for in vivo testing. Optimization of potency was guided by structure-based insights, specifically to replace an ester moiety and introduce polar directional hydrogen bonding interactions in the core of the molecule. By introducing polar enthalpic interactions in this series of inhibitors, the overall beneficial physicochemical properties were maintained. These physicochemical properties translated to excellent drug-like properties beyond potency. In a murine model of rheumatoid arthritis, treatment of mice with selective inhibitors of MMP-13 resulted in a statistically significant reduction in the mean arthritic score vs control when dosed over a 14 day period.

2.
Bioorg Med Chem Lett ; 26(21): 5277-5283, 2016 11 01.
Article in English | MEDLINE | ID: mdl-27692854

ABSTRACT

Compound 1 ((4-amino-3,5-dichlorophenyl)-1-(4-methylpiperidin-1-yl)-4-(2-nitroimidazol-1-yl)-1-oxobutane-2-sulfonamido) was discovered to be a 690nM antagonist of human CCR10 Ca2+ flux. Optimization delivered (2R)-4-(2-cyanopyrrol-1-yl)-S-(1H-indol-4-yl)-1-(4-methylpiperidin-1-yl)-1-oxobutane-2-sulfonamido (eut-22) that is 300 fold more potent a CCR10 antagonist than 1 and eliminates potential toxicity, mutagenicity, and drug-drug-interaction liabilities often associated with nitroaryls and anilines. eut-22 is highly selective over other GPCR's, including a number of other chemokine receptors. Finally, eut-22 is efficacious in the murine DNFB model of contact hypersensitivity. The efficacy of this compound provides further evidence for the role of CCR10 in dermatological inflammatory conditions.


Subject(s)
Amides/pharmacology , Dermatitis, Contact/drug therapy , Dinitrofluorobenzene/toxicity , Disease Models, Animal , Receptors, CCR10/antagonists & inhibitors , Amides/chemistry , Amides/therapeutic use , Animals , Carboxylic Acids/chemistry , Cell Line , Humans , Mice , Structure-Activity Relationship
4.
Bioorg Med Chem Lett ; 22(23): 7189-93, 2012 Dec 01.
Article in English | MEDLINE | ID: mdl-23084902

ABSTRACT

This paper details exploration of a class of triazole-based cathepsin S inhibitors originally reported by Ellman and co-workers. SAR studies involving modifications across the whole inhibitor provide a perspective on the strengths and weaknesses of this class of inhibitors. In addition, we put the unique characteristics of this class of compounds into perspective with other classes of cathepsin S inhibitors.


Subject(s)
Amides/chemistry , Cathepsins/antagonists & inhibitors , Protease Inhibitors/chemistry , Thiophenes/chemistry , Triazoles/chemistry , Cathepsins/metabolism , Half-Life , Humans , Microsomes, Liver/metabolism , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacokinetics , Protein Binding , Structure-Activity Relationship , Thiophenes/chemical synthesis , Thiophenes/pharmacokinetics , Triazoles/chemical synthesis , Triazoles/pharmacokinetics
5.
J Med Chem ; 54(23): 8174-87, 2011 Dec 08.
Article in English | MEDLINE | ID: mdl-22017539

ABSTRACT

Matrix metalloproteases (MMPs) play an important role in cartilage homeostasis under both normal and inflamed disease states and, thus, have become attractive targets for the treatment of arthritic diseases. Herein, we describe the identification of a potent, selective MMP-13 inhibitor, developed using fragment-based structure-guided lead identification and optimization techniques. Virtual screening methods identified a novel, indole-based MMP-13 inhibitor that bound into the S1' pocket of the protein exhibiting a novel interaction pattern hitherto not observed in MMP-13 inhibitors. X-ray crystallographic structures were used to guide the elaboration of the fragment, ultimately leading to a potent inhibitor that was >100-fold selective over nine other MMP isoforms tested.


Subject(s)
Indoles/chemical synthesis , Matrix Metalloproteinase Inhibitors , Crystallography, X-Ray , Humans , Indoles/chemistry , Matrix Metalloproteinase 13/chemistry , Models, Molecular , Recombinant Proteins/antagonists & inhibitors , Recombinant Proteins/chemistry , Structure-Activity Relationship
6.
Bioorg Med Chem Lett ; 20(17): 5039-43, 2010 Sep 01.
Article in English | MEDLINE | ID: mdl-20675133

ABSTRACT

SAR studies to improve the selectivity and metabolic stability of a class of recently discovered MMP-13 inhibitors are reported. Improved selectivity was achieved by modifying interactions with the S1' pocket. Metabolic stability was improved through reduction of inhibitor lipophilicity. This translated into lower in vivo clearance for the preferred compound.


Subject(s)
Matrix Metalloproteinase Inhibitors , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Chelating Agents/chemistry , Chelating Agents/pharmacology , Structure-Activity Relationship , Zinc/chemistry
7.
Bioorg Med Chem Lett ; 19(23): 6780-3, 2009 Dec 01.
Article in English | MEDLINE | ID: mdl-19836229

ABSTRACT

A series of potent piperidine-linked cytosine derivatives were prepared as inhibitors of deoxycytidine kinase (dCK). Compound 9h was discovered to be a potent inhibitor of dCK and shows a good combination of cellular potency and pharmacokinetic parameters. Compound 9h blocks the incorporation of radiolabeled cytosine into mouse T-cells in vitro, as well as in vivo in mice following a T-cell challenge.


Subject(s)
Deoxycytidine Kinase/antagonists & inhibitors , Flucytosine/pharmacology , Protein Kinase Inhibitors/pharmacology , Animals , Drug Design , Flucytosine/chemical synthesis , Flucytosine/chemistry , Humans , Mice , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Stereoisomerism , Structure-Activity Relationship
8.
Bioorg Med Chem Lett ; 19(23): 6784-7, 2009 Dec 01.
Article in English | MEDLINE | ID: mdl-19836232

ABSTRACT

A series of deoxycytidine kinase inhibitors was simultaneously optimized for potency and PK properties. A co-crystal structure then allowed merging this series with a high throughput screening hit to afford a highly potent, selective and orally bioavailable inhibitor, compound 10. This compound showed dose dependent inhibition of deoxycytidine kinase in vivo.


Subject(s)
Deoxycytidine Kinase/antagonists & inhibitors , Deoxycytidine/analogs & derivatives , Drug Design , Protein Kinase Inhibitors/pharmacology , Deoxycytidine/chemical synthesis , Deoxycytidine/chemistry , Deoxycytidine/pharmacology , Dose-Response Relationship, Drug , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Stereoisomerism , Structure-Activity Relationship
9.
Bioorg Med Chem Lett ; 19(18): 5321-4, 2009 Sep 15.
Article in English | MEDLINE | ID: mdl-19692239

ABSTRACT

Discovery and optimization of potency and selectivity of a non-Zn-chelating MMP-13 inhibitor with the aid of protein co-crystal structural information is reported. This inhibitor was observed to have a binding mode distinct from previously published MMP-13 inhibitors. Potency and selectivity were improved by extending the hit structure out from the active site into the S1' pocket.


Subject(s)
Chelating Agents/pharmacology , Matrix Metalloproteinase 13/metabolism , Matrix Metalloproteinase Inhibitors , Protease Inhibitors/pharmacology , Catalytic Domain , Chelating Agents/chemistry , Matrix Metalloproteinase 13/chemistry , Models, Molecular , Protease Inhibitors/chemistry , Protein Binding , Structure-Activity Relationship
10.
J Org Chem ; 70(18): 7331-7, 2005 Sep 02.
Article in English | MEDLINE | ID: mdl-16122255

ABSTRACT

[reaction: see text] Imidazo[5,1-f][1,2,4]triazinones, as isosteres of purine, are of interest for pharmaceutical research. The syntheses reported in the literature generally require several steps. We report a novel method to access a broad range of diversely substituted derivatives. The key step is the electrophilic N-amination of 3H-imidazoles containing a 4-carbonyl group. Several different substituted imidazoles have been N-aminated in this manner. The resulting N-aminoimidazoles were cyclized under different conditions to the corresponding imidazotriazinones, which allowed for additional diversification. This novel method was applied in a formal synthesis of vardenafil, a well-known representative of this class of compounds. Furthermore, we report the first synthesis of a 7-aryl-imidazotriazinone via bromination of an unsubstituted imidazotriazinone followed by a Suzuki coupling.


Subject(s)
Imidazoles/chemical synthesis , Phosphodiesterase Inhibitors/chemical synthesis , Piperazines/chemical synthesis , Sulfones/chemical synthesis , Triazines/chemical synthesis , Vardenafil Dihydrochloride
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