ABSTRACT
The incorporation of a carboxylic acid within in a series of 3-amido-4-aryl substituted piperidines (represented by general structure 32) led to the discovery of potent, zwitterionic, renin inhibitors with improved off-target profiles (CYP3A4 time-dependent inhibition and hERG affinity) relative to analogous non-zwitterionic inhibitors of the past (i.e., 3). Strategies to address the oral absorption of these zwitterions are also discussed within.
Subject(s)
Protease Inhibitors/chemical synthesis , Renin/antagonists & inhibitors , Administration, Oral , Animals , Catalytic Domain , Computer Simulation , Dogs , Drug Evaluation, Preclinical , Humans , Piperidines/chemical synthesis , Piperidines/chemistry , Piperidines/pharmacokinetics , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacokinetics , Rats , Rats, Sprague-Dawley , Renin/metabolism , Structure-Activity RelationshipABSTRACT
The discovery of novel and selective inhibitors of human 5-lipoxygenase (5-LO) is described. These compounds are potent, orally bioavailable, and active at inhibiting leukotriene biosynthesis in vivo in a dog PK/PD model. A major focus of the optimization process was to reduce affinity for the human ether-a-go-go gene potassium channel while preserving inhibitory potency on 5-LO. These efforts led to the identification of inhibitor (S)-16 (MK-0633, setileuton), a compound selected for clinical development for the treatment of respiratory diseases.
ABSTRACT
Caspase-3 is a cysteinyl protease that mediates apoptotic cell death. Its inhibition may have an important impact on the treatment of several degenerative diseases. Here we report the synthesis of reversible inhibitors via a solid-support palladium-catalyzed amination of 3-bromopyrazinones and the discovery of a pan-caspase reversible inhibitor.
Subject(s)
Caspase Inhibitors , Palladium/chemistry , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , Pyrazines/chemical synthesis , Pyrazines/pharmacology , Amination , Catalysis , Cell Line , Chromatography, High Pressure Liquid , Humans , Indicators and Reagents , Mass Spectrometry , Recombinant Proteins/chemistry , Structure-Activity RelationshipABSTRACT
Leukotriene biosynthesis inhibitors have potential as therapeutic agents for asthma and inflammatory diseases. A novel series of substituted coumarin derivatives has been synthesized and the structure-activity relationship was evaluated with respect to their ability to inhibit the formation of leukotrienes via the human 5-lipoxygenase enzyme.
Subject(s)
Coumarins/pharmacology , Enzyme Inhibitors/pharmacology , Lipoxygenase Inhibitors , Coumarins/chemical synthesis , Coumarins/chemistry , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Molecular Structure , Structure-Activity RelationshipABSTRACT
Caspase 3 is a cysteinyl protease that mediates apoptotic cell death. Its inhibition may have an important impact in the treatment of several degenerative diseases. The P1 aspartic acid residue is a required element of recognition for this enzyme that was maintained constant along with the adjacent natural valine as the P2 group. The thiobenzylmethylketone warhead on the aspartate was conveniently handled through solid-phase synthesis allowing modification in the P3 region that eventually led to simpler derivatives with increased potency against caspase 3. The key to such an effect is the introduction of hydroxyl group alpha to the P3 carbonyl.
Subject(s)
Caspase Inhibitors , Dipeptides/chemical synthesis , Ketones/chemical synthesis , Aspartic Acid , Caspase 3 , Combinatorial Chemistry Techniques , Dipeptides/pharmacology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Humans , Hydrogen Bonding , Hydrophobic and Hydrophilic Interactions , Inhibitory Concentration 50 , Ketones/pharmacology , Recombinant Proteins , Structure-Activity Relationship , ValineABSTRACT
A series of potent and selective inhibitors of the inducible microsomal PGE2 synthase (mPGES-1) has been developed based on the indole FLAP inhibitor MK-886. Compounds 23 and 30 inhibit mPGES-1 with potencies in the low nanomolar range and with selectivities of at least 100-fold compared to their inhibition of mPGES-2, thromboxane synthase and binding affinity to FLAP. They also block the production of PGE2 in cell based assays but with a decreased potency and more limited selectivity compared to the enzyme assays.
Subject(s)
Cyclooxygenase Inhibitors/chemical synthesis , Cyclooxygenase Inhibitors/pharmacology , Indoles/chemical synthesis , Indoles/pharmacology , Intramolecular Oxidoreductases/antagonists & inhibitors , Cell Line, Tumor , Cell Proliferation/drug effects , Cyclooxygenase Inhibitors/chemistry , Humans , Indoles/chemistry , Microsomes/enzymology , Prostaglandin-E Synthases , Structure-Activity RelationshipABSTRACT
A robust method for the solid phase synthesis of a series of selective caspase-3 peptide inhibitors is described. The inhibitors can be obtained after cleavage from the solid support without further purification.
Subject(s)
Caspase Inhibitors , Oligopeptides/chemical synthesis , Oligopeptides/pharmacology , Caspase 3 , Cell Line , Cell Survival/drug effects , Combinatorial Chemistry Techniques , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Humans , Inhibitory Concentration 50ABSTRACT
The discovery of a series of potent, selective and reversible dipeptidyl caspase-3 inhibitors are reported. The iterative discovery process of using combinatorial chemistry, parallel synthesis, moleculare modelling and structural biology will be discussed.
Subject(s)
Aspartic Acid/chemistry , Caspase Inhibitors , Dipeptides , Enzyme Inhibitors , Ketones , Binding Sites , Caspase 3 , Cells, Cultured , Combinatorial Chemistry Techniques , Dipeptides/chemical synthesis , Dipeptides/pharmacology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Humans , Ketones/chemical synthesis , Ketones/pharmacology , Models, Molecular , Structure-Activity Relationship , Substrate SpecificityABSTRACT
Caspase-3 is a cysteinyl protease that mediates apoptotic cell death. Its inhibition may have an important impact in the treatment of several degenerative diseases. Since P(1) aspartic acid is a required element of recognition for this enzyme, a library of capped aspartyl aldehydes was synthesized using solid-phase chemistry. The 5-bromonicotinamide derivative of the aspartic acid aldehyde was identified to be an inhibitor of caspase-3. Substitution at the 5-position of the pyridine ring and conversion of the aldehyde to ketones led to a series of potent inhibitors of caspase-3.
Subject(s)
Caspase Inhibitors , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Ketones/chemical synthesis , Ketones/pharmacology , Aldehydes/chemical synthesis , Aldehydes/pharmacology , Aspartic Acid/chemistry , Caspase 3 , Cell Line , DNA Fragmentation/drug effects , Enzyme-Linked Immunosorbent Assay , Humans , Indicators and Reagents , Peptide Library , Pyridines/chemistryABSTRACT
The introduction of a hydroxyl group into the 5-position of the diaryl furanone system provides highly selective inhibitors of cyclooxygenase-2. These molecules can be converted into their sodium salts which are water soluble, facilitating intravenous formulation. These salts show excellent potency in rat models of pain, fever and inflammation.