ABSTRACT
Novel bicyclic adenosine A(2A) antagonists with an aminoquinazoline moiety were designed and synthesized. The optimization of the initial lead compound based on in vitro and in vivo activity has led to the discovery of a potent and selective class of adenosine A(2A) antagonists. The structure-activity relationships of this novel series of bicyclic aminoquinazoline derivatives as adenosine A(2A) antagonists are described in detail.
Subject(s)
Adenosine A2 Receptor Antagonists/chemistry , Quinazolines/chemistry , Receptor, Adenosine A2A/chemistry , Adenosine A2 Receptor Antagonists/chemical synthesis , Adenosine A2 Receptor Antagonists/pharmacokinetics , Animals , Binding Sites , Drug Design , Half-Life , Humans , Inhibitory Concentration 50 , Molecular Docking Simulation , Protein Structure, Tertiary , Quinazolines/chemical synthesis , Quinazolines/pharmacokinetics , Rats , Receptor, Adenosine A2A/metabolism , Structure-Activity RelationshipABSTRACT
We report the discovery of a novel series of DGAT1 inhibitors in the benzimidazole class with a piperdinyl-oxy-cyclohexanecarboxylic acid moiety. This novel series possesses significantly improved selectivity against the A2A receptor, no ACAT1 off-target activity at 10 µM, and higher aqueous solubility and free fraction in plasma as compared to the previously reported pyridyl-oxy-cyclohexanecarboxylic acid series. In particular, 5B was shown to possess an excellent selectivity profile by screening it against a panel of more than 100 biological targets. Compound 5B significantly reduces lipid excursion in LTT in mouse and rat, demonstrates DGAT1 mediated reduction of food intake and body weight in mice, is negative in a 3-strain Ames test, and appears to distribute preferentially in the liver and the intestine in mice. We believe this lead series possesses significant potential to identify optimized compounds for clinical development.
ABSTRACT
Diacylglycerol acyltransferase 1 (DGAT1) presents itself as a potential therapeutic target for obesity and diabetes for its important role in triglyceride biosynthesis. Herein we report the rational design of a novel class of DGAT1 inhibitors featuring a benzomorpholine core (23n). SAR exploration yielded compounds with good potency and selectivity as well as reasonable physical and pharmacokinetic properties. This class of DGAT1 inhibitors was tested in rodent models to evaluate DGAT1 inhibition as a novel approach for the treatment of metabolic diseases. Compound 23n conferred weight loss and a reduction in liver triglycerides when dosed chronically in mice with diet-induced obesity and depleted serum triglycerides following a lipid challenge.
ABSTRACT
Herein we report the design and synthesis of a series of novel bicyclic DGAT1 inhibitors with a carboxylic acid moiety. The optimization of the initial lead compound 7 based on in vitro and in vivo activity led to the discovery of potent indoline and quinoline classes of DGAT1 inhibitors. The structure-activity relationship studies of these novel series of bicyclic carboxylic acid derivatives as DGAT1 inhibitors are described.
Subject(s)
Carboxylic Acids/pharmacology , Diacylglycerol O-Acyltransferase/antagonists & inhibitors , Drug Discovery , Enzyme Inhibitors/pharmacology , Quinolones/pharmacology , Animals , Carboxylic Acids/chemical synthesis , Carboxylic Acids/chemistry , Diacylglycerol O-Acyltransferase/metabolism , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Mice , Models, Molecular , Molecular Structure , Quinolones/chemical synthesis , Quinolones/chemistry , Structure-Activity RelationshipABSTRACT
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
We report the design and synthesis of a series of novel DGAT1 inhibitors in the benzimidazole class with a pyridyl-oxy-cyclohexanecarboxylic acid moiety. In particular, compound 11A is a potent DGAT1 inhibitor with excellent selectivity against ACAT1. Compound 11A significantly reduces triglyceride excursion in lipid tolerance tests (LTT) in both mice and dogs at low plasma exposure. An in vivo study in mice with des-fluoro analogue 10A indicates that this series of compounds appears to distribute in intestine preferentially over plasma. The propensity to target intestine over plasma could be advantageous in reducing potential side effects since lower circulating levels of drug are required for efficacy. However, in the preclinical species, compound 11A undergoes cis/trans epimerization in vivo, which could complicate further development due to the presence of an active metabolite.
ABSTRACT
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
Optimization of oxazole-based PDE4 inhibitors has led to the discovery of a series of quinolyl oxazoles, with 4-benzylcarboxamide and 5-α-aminoethyl groups which exhibit picomolar potency against PDE4. Selectivity profiles and in vivo biological activity are also reported.
Subject(s)
Anti-Inflammatory Agents/chemical synthesis , Cyclic Nucleotide Phosphodiesterases, Type 4/chemistry , Oxazoles/chemical synthesis , Phosphodiesterase 4 Inhibitors/chemical synthesis , Quinolines/chemical synthesis , Animals , Anti-Inflammatory Agents/pharmacology , Cyclic N-Oxides/chemistry , Cyclic Nucleotide Phosphodiesterases, Type 4/metabolism , Drug Discovery , Humans , Models, Molecular , Oxazoles/pharmacology , Phosphodiesterase 4 Inhibitors/pharmacology , Quinolines/chemistry , Quinolines/pharmacology , Rats , Structure-Activity Relationship , Tumor Necrosis Factor-alpha/antagonists & inhibitorsABSTRACT
The echinocandins are a class of semisynthetic natural products that target ß-1,3-glucan synthase (GS). Their proven clinical efficacy combined with minimal safety issues has made the echinocandins an important asset in the management of fungal infection in a variety of patient populations. However, the echinocandins are delivered only parenterally. A screen for antifungal bioactivities combined with mechanism-of-action studies identified a class of piperazinyl-pyridazinones that target GS. The compounds exhibited in vitro activity comparable, and in some cases superior, to that of the echinocandins. The compounds inhibit GS in vitro, and there was a strong correlation between enzyme inhibition and in vitro antifungal activity. In addition, like the echinocandins, the compounds caused a leakage of cytoplasmic contents from yeast and produced a morphological response in molds characteristic of GS inhibitors. Spontaneous mutants of Saccharomyces cerevisiae with reduced susceptibility to the piperazinyl-pyridazinones had substitutions in FKS1. The sites of these substitutions were distinct from those conferring resistance to echinocandins; likewise, echinocandin-resistant isolates remained susceptible to the test compounds. Finally, we present efficacy and pharmacokinetic data on an example of the piperazinyl-pyridazinone compounds that demonstrated efficacy in a murine model of Candida glabrata infection.
Subject(s)
Antifungal Agents/pharmacology , Glucosyltransferases/antagonists & inhibitors , Animals , Antifungal Agents/chemistry , Candida glabrata/drug effects , Candida glabrata/enzymology , Candida glabrata/pathogenicity , Candidiasis/drug therapy , Male , Mice , Molecular Structure , Piperazines/chemistry , Piperazines/pharmacology , Pyridazines/chemistry , Pyridazines/pharmacology , Saccharomyces cerevisiae/drug effects , Saccharomyces cerevisiae/enzymologyABSTRACT
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 mild catalytic system to access diversely functionalized benzylic sulfonamides has been developed. Palladium-catalyzed alpha-arylation by Negishi cross-coupling of sulfonamide-stabilized anions and a wide range of aryl iodides, bromides, and triflates constitutes a practical strategy for the synthesis of various benzylic sulfonamides.
Subject(s)
Benzene Derivatives/chemical synthesis , Palladium/chemistry , Sulfonamides/chemical synthesis , Benzene Derivatives/chemistry , Catalysis , Combinatorial Chemistry Techniques , Molecular Structure , Sulfonamides/chemistryABSTRACT
Fungi can cause life threatening diseases, particularly in patients with weakened immune systems. While treatment options are available for these individuals, dose limiting toxicity and the appearance of drug resistant organisms are growing problems. Therefore, the identification, development, and registration of new, safe, and efficacious agents are needed. Herein, we review recent developments in the field of antifungal drug discovery. We focus on recently launched drugs (triazoles and echinocandins), agents in clinical development, and compounds in discovery.
Subject(s)
Antifungal Agents/chemistry , Antifungal Agents/therapeutic use , Mycoses/drug therapy , Antifungal Agents/pharmacology , Drug Design , Fungi/drug effects , Humans , Molecular StructureABSTRACT
Substituted quinolyl oxazoles were discovered as a novel and highly potent series of phosphodiesterase 4 (PDE4) inhibitors. Structure-activity relationship studies revealed that the oxazole core, with 4-carboxamide and 5-aminomethyl groups, is a novel PDE4 inhibitory pharmacophore. Selectivity profiles and in vivo biological activity are also reported.