ABSTRACT
The optimization of oxazole-based PDE4 inhibitor 1 has led to the identification of both oral (compound 16) and inhaled (compound 34) PDE4 inhibitors. Selectivity against PDE10/PDE11, off target screening, and in vivo activity in the rat are discussed.
Subject(s)
Cyclic Nucleotide Phosphodiesterases, Type 4/chemistry , Oxazoles/chemistry , Proline/analogs & derivatives , Quinolines/chemical synthesis , Administration, Oral , Animals , Cyclic Nucleotide Phosphodiesterases, Type 4/metabolism , Drug Evaluation, Preclinical , Half-Life , Inhalation , Oxazoles/chemical synthesis , Oxazoles/pharmacokinetics , Phosphodiesterase 4 Inhibitors/chemical synthesis , Phosphodiesterase 4 Inhibitors/chemistry , Phosphodiesterase 4 Inhibitors/pharmacokinetics , Proline/chemical synthesis , Proline/chemistry , Proline/pharmacokinetics , Quinolines/chemistry , Quinolines/pharmacokinetics , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
The structure-activity relationship studies of a novel series of carboxylic acid derivatives of pyridine-carboxamides as DGAT-1 inhibitors is described. The optimization of the initial lead compound 6 based on in vitro and in vivo activity led to the discovery of key compounds 10j and 17h.
Subject(s)
Amides/pharmacology , Diacylglycerol O-Acyltransferase/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Pyridines/pharmacology , Animals , Diacylglycerol O-Acyltransferase/metabolism , Enzyme Inhibitors/chemistry , Humans , Mice , Structure-Activity RelationshipABSTRACT
A detailed structure-activity relationship study of a novel series of pyridazine-based small molecule glucan synthase inhibitors is described. The optimization of the PK profile of this series led to the discovery of compound 11g, which demonstrated in vivo potency ip in a lethal fungal infection model.
Subject(s)
Antifungal Agents/chemistry , Enzyme Inhibitors/chemistry , Glucosyltransferases/antagonists & inhibitors , Pyridazines/chemistry , Sulfonamides/chemistry , Animals , Antifungal Agents/pharmacokinetics , Antifungal Agents/therapeutic use , Candida/drug effects , Candidiasis/drug therapy , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/therapeutic use , Glucosyltransferases/metabolism , Half-Life , Mice , Microbial Sensitivity Tests , Pyridazines/pharmacokinetics , Pyridazines/therapeutic use , Rats , Structure-Activity Relationship , Sulfonamides/pharmacokinetics , Sulfonamides/therapeutic useABSTRACT
The structure-activity relationship studies of a novel sulfonylurea series of piperazine pyridazine-based small molecule glucan synthase inhibitors is described. The optimization of PK profiles within the series led to the discovery of several compounds with improved pharmacokinetic profiles which demonstrated in vitro potency against clinically relevant strains. However, the advancement of compounds from this series into a non-lethal systemic fungal infection model failed to show in vivo efficacy.
Subject(s)
Antifungal Agents/chemistry , Enzyme Inhibitors/chemistry , Glucosyltransferases/antagonists & inhibitors , Lead/chemistry , Piperazines/chemistry , Pyridazines/chemistry , Sulfonylurea Compounds/chemistry , Animals , Antifungal Agents/pharmacology , Candida/drug effects , Cell Line , Enzyme Inhibitors/pharmacology , Humans , Molecular Structure , Piperazine , Pyridazines/pharmacology , Rats , Structure-Activity Relationship , Sulfonylurea Compounds/pharmacologyABSTRACT
A novel series of pyridazinone analogs has been developed as potent ß-1,3-glucan synthase inhibitors through structure-activity relationship study of the lead 5-[4-(benzylsulfonyl)piperazin-1-yl]-4-morpholino-2-phenyl-pyridazin-3(2H)-one (1). The effect of changes to the core structure is described in detail. Optimization of the sulfonamide moiety led to the identification of important compounds with much improved systematic exposure while retaining good antifungal activity against the fungal strains Candida glabrata and Candida albicans.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Glucosyltransferases/antagonists & inhibitors , Pyridazines/chemical synthesis , Pyridazines/pharmacology , Antifungal Agents/chemical synthesis , Antifungal Agents/chemistry , Antifungal Agents/pharmacology , Candida albicans/drug effects , Candida glabrata/drug effects , Enzyme Inhibitors/chemistry , Molecular Structure , Pyridazines/chemistry , Structure-Activity RelationshipABSTRACT
A structure-activity relationship study of the lead 5-[4-(benzylsulfonyl)piperazin-1-yl]-4-morpholino-2-phenyl-pyridazin-3(2H)-one 1 has resulted in the identification of 2-(3,5-difluorophenyl)-4-(3-fluorocyclopentyloxy)-5-[4-(isopropylsulfonyl)piperazin-1-yl]-pyridazin-3(2H)-one 11c as a ß-1,3-glucan synthase inhibitor. Compound 11c exhibited significant efficacy in an in vivo mouse model of Candida glabrata infection.
Subject(s)
Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Glucosyltransferases/antagonists & inhibitors , Pyridazines/chemistry , Pyridazines/pharmacology , Enzyme Inhibitors/chemical synthesis , Pyridazines/chemical synthesis , Structure-Activity RelationshipABSTRACT
A structure-activity relationship study of the lead piperazinylcarbonylpiperidine compound 3 resulted in the identification of 4-benzimidazolyl-piperidinylcarbonyl-piperidine 6h as a histamine-3 (H(3)) receptor antagonist. Additional optimization of 6h led to the identification of compounds 11i-k with K(i) Subject(s)
Histamine H3 Antagonists/chemical synthesis
, Histamine H3 Antagonists/pharmacology
, Piperidines/chemical synthesis
, Piperidines/pharmacology
, Structure-Activity Relationship
ABSTRACT
The syntheses and structure-activity relationships of the tartrate-based TACE inhibitors are discussed. The optimization of both the prime and non-prime sites led to compounds with picomolar activity. Several analogs demonstrated good rat pharmacokinetics.
Subject(s)
ADAM Proteins/antagonists & inhibitors , Protease Inhibitors/chemistry , Tartrates/chemistry , ADAM Proteins/metabolism , ADAM17 Protein , Animals , Binding Sites , Computer Simulation , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacokinetics , Rats , Structure-Activity Relationship , Tartrates/chemical synthesis , Tartrates/pharmacokineticsABSTRACT
A strategy to overcome the side effect liabilities of oral PDE4 inhibitors has been to deliver the drugs by inhalation. In this report, we identify 1-[[5-(1(S)-aminoethly)-2-[8-methoxy-2-(triflurormethyl)-5-quinolinyl]-4-oxazolyl] carbonyl]-4(R)-[(cyclopropylcarbonyl)amino]-L-proline, ethyl ester xinafoate salt, (COMPOUND 1) as a potent and selective inhibitor of PDE4 with biological and pharmacokinetic properties suitable for delivery by the inhaled route. COMPOUND 1 potently inhibits human PDE4 (IC(50)=70pM) with little or no activity against other PDEs. It is highly potent against PDE4B and PDE4D which are important isoforms of PDE4 controlling inflammation and airway functions. In an allergen-challenged Brown Norway rat model of asthma, COMPOUND 1 inhibited the late phase influx of inflammatory cells and reductions in lung function following its administration by the intratracheal or nose-only routes of administration. Important differences were seen between intratracheal COMPOUND 1 and our previously published results with the oral PDE4 inhibitor roflumilast (Celly et al., 2005), as COMPOUND 1 rapidly (within 1h) reversed the decline in lung function when it was given therapeutically to rats already challenged with antigen. COMPOUND 1 was weakly active by the oral route which is a finding consistent with results showing this compound has poor oral bioavailability in animals. Positive interactions between COMPOUND 1 and albuterol, and COMPOUND 1 and mometasone furoate were seen on the improvement in lung functions in allergen-challenged rats. These results identify COMPOUND 1 as a potent and selective inhibitor of PDE4 with properties suitable for delivery by inhalation.
Subject(s)
Anti-Allergic Agents/administration & dosage , Anti-Allergic Agents/pharmacology , Asthma/drug therapy , Phosphodiesterase 4 Inhibitors/administration & dosage , Phosphodiesterase 4 Inhibitors/pharmacology , Proline/analogs & derivatives , Quinolines/pharmacology , Administration, Inhalation , Aerosols , Animals , Anti-Allergic Agents/blood , Anti-Allergic Agents/pharmacokinetics , Anti-Inflammatory Agents/therapeutic use , Asthma/immunology , Asthma/physiopathology , Biological Availability , Bronchoalveolar Lavage Fluid/cytology , Bronchodilator Agents/therapeutic use , Cyclic Nucleotide Phosphodiesterases, Type 3/metabolism , Cyclic Nucleotide Phosphodiesterases, Type 4/metabolism , Drug Synergism , Half-Life , Humans , Leukocytes/drug effects , Leukocytes/enzymology , Leukocytes/metabolism , Phosphodiesterase 4 Inhibitors/blood , Phosphodiesterase 4 Inhibitors/pharmacokinetics , Powders , Proline/pharmacology , Rats , Rats, Inbred BN , Tumor Necrosis Factor-alpha/metabolismABSTRACT
A novel series of TNF-alpha convertase (TACE) inhibitors which are non-hydroxamate have been discovered. These compounds are bis-amides of L-tartaric acid (tartrate) and coordinate to the active site zinc in a tridentate manner. They are selective for TACE over other MMP's. We report the first X-ray crystal structure for a tartrate-based TACE inhibitor.
Subject(s)
ADAM Proteins/antagonists & inhibitors , ADAM Proteins/metabolism , Drug Discovery , Protease Inhibitors/chemistry , Tartrates/chemistry , Tumor Necrosis Factor-alpha/metabolism , ADAM17 Protein , Binding Sites , Combinatorial Chemistry Techniques , Crystallography, X-Ray , Drug Discovery/methods , Humans , Protease Inhibitors/metabolism , Protease Inhibitors/pharmacology , Tartrates/metabolism , Tartrates/pharmacologyABSTRACT
A novel series of histamine H3 receptor antagonists based on the 4-[(1H-imidazol-4-yl)methyl]piperidine template displaying low CYP2D6 and CYP3A4 inhibitory profiles has been identified. Structural features responsible for the reduction of P450 activity, a typical liability of 4-substituted imidazoles, have been established.
Subject(s)
Cytochrome P-450 Enzyme Inhibitors , Enzyme Inhibitors/pharmacology , Histamine Antagonists/pharmacology , Imidazoles/pharmacology , Piperidines/pharmacology , Receptors, Histamine H3/drug effects , Animals , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Guinea Pigs , Haplorhini , Histamine Antagonists/chemical synthesis , Histamine Antagonists/chemistry , Humans , Imidazoles/chemical synthesis , Imidazoles/chemistry , Molecular Structure , Piperidines/chemical synthesis , Piperidines/chemistry , Rats , Structure-Activity Relationship , Tissue DistributionABSTRACT
Bipiperidine amide 1 has been identified as a CC chemokine receptor 3 (CCR3) antagonist. Optimization of its structure-activity relationship has resulted in the identification of cis (R,R)-4-[(3,4-dichlorophenyl)methyl]-3-hydroxymethyl-1'(6-quinolinylcarbonyl)-1,4'-bipiperidine 14n, which exhibits potent receptor affinity and inhibition of both calcium flux and eosinophil chemotaxis.
Subject(s)
Amides/chemical synthesis , Amides/pharmacology , Piperidines/chemical synthesis , Piperidines/pharmacology , Receptors, Chemokine/antagonists & inhibitors , Animals , Humans , Molecular Structure , Receptors, CCR3 , Structure-Activity RelationshipABSTRACT
A novel series of dual NK(1)/NK(2) receptor antagonists, based on the 2-oxo-(1,4'-bipiperidine) template, has been prepared. Compound 10R is a potent dual NK(1)/NK(2) antagonist and demonstrates excellent in vivo activity and good oral plasma levels in the dog.