ABSTRACT
A series of 2-(1H-pyrazol-1-yl)pyridines are described as inhibitors of ALK5 (TGFß receptor I kinase). Modeling compounds in the ALK5 kinase domain enabled some optimization of potency via substitutions on the pyrazole core. One of these compounds PF-03671148 gave a dose dependent reduction in TGFß induced fibrotic gene expression in human fibroblasts. A similar reduction in fibrotic gene expression was observed when PF-03671148 was applied topically in a rat wound repair model. Thus these compounds have potential utility for the prevention of dermal scarring.
Subject(s)
Cicatrix/prevention & control , Drug Discovery , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Pyridines/chemistry , Pyridines/pharmacology , Receptors, Transforming Growth Factor beta/antagonists & inhibitors , Skin/drug effects , Animals , Models, Molecular , Phosphorylation , Rats , Receptor, Transforming Growth Factor-beta Type IABSTRACT
A series of pantolactam based compounds were identified as potent antagonists for the androgen receptor (AR). Those that possessed properties suitable for topical delivery were evaluated in the validated Hamster Ear Model. Several compounds were found to be efficacious in reducing wax esters, a major component of sebum, initiating further preclinical work on these compounds.
Subject(s)
Androgen Receptor Antagonists/pharmacology , Esters/metabolism , Lactams/pharmacology , Sebum/drug effects , Waxes/metabolism , Administration, Topical , Androgen Receptor Antagonists/chemical synthesis , Androgen Receptor Antagonists/chemistry , Animals , Cricetinae , Crystallography, X-Ray , Dose-Response Relationship, Drug , Esters/chemistry , Lactams/chemical synthesis , Lactams/chemistry , Models, Animal , Models, Molecular , Molecular Structure , Receptors, Androgen/metabolism , Sebum/metabolism , Stereoisomerism , Structure-Activity Relationship , Waxes/chemistryABSTRACT
A series of acyloxyalkyl and amidooxyalkyl ketones appended to a carbobenzyloxy aspartic acid core have been prepared. The most potent of these new inhibitors was 4i with a K(i) of 0.5 microM. These two series provide an improved understanding of the binding requirements for the hydrophobic prime side of ICE.
Subject(s)
Caspase Inhibitors , Cysteine Proteinase Inhibitors/pharmacology , Ketones/pharmacology , Humans , Models, Molecular , Monocytes/drug effectsABSTRACT
Succinic acid amides have been found to be effective P2-P3 scaffold replacements for peptidic ICE inhibitors. Heteroarylalkyl fragments occupying the P4 position provided access to compounds with nM affinities. Utilization of an acylal prodrug moiety was required to overcome biopharmaceutical issues which led to the identification of 17f, a potential clinical candidate.
Subject(s)
Amides/chemistry , Caspase Inhibitors , Cysteine Proteinase Inhibitors/pharmacology , Succinic Acid/chemistry , Cysteine Proteinase Inhibitors/chemistry , Cysteine Proteinase Inhibitors/pharmacokinetics , Half-Life , Magnetic Resonance Spectroscopy , Models, Molecular , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The first examples of thioether-substituted benzonitriles as potential soft-drug androgen receptor antagonists are reported. A number of 4-(alkylthio)- and of 4-(arylthio)-benzonitrile analogs were evaluated in human androgen receptor binding and cellular functional assays. Analogs with potent in vitro binding and cellular activities were evaluated for topical in vivo efficacy in the Golden Syrian hamster ear model. Analogs from both the 4-(alkylthio)- and of 4-(arylthio)-benzonitrile series showed moderate reduction of wax esters in vivo.
Subject(s)
Androgen Antagonists/chemistry , Androgen Receptor Antagonists , Nitriles/chemical synthesis , Nitriles/pharmacology , Sebum/drug effects , Sebum/metabolism , Androgen Antagonists/pharmacology , Animals , Cell Line , Cricetinae , Humans , Insecta , Male , Mesocricetus , Protein Binding/drug effects , Protein Binding/physiology , Receptors, Androgen/metabolismABSTRACT
A series of diphenyl ethers was prepared and evaluated for androgen receptor antagonist activity in human androgen receptor binding and cellular functional assays. Analogs with potent in vitro activities were evaluated for topical in vivo efficacy in the Golden Syrian Hamster ear model. Several compounds showed reduction in wax esters in this validated animal model.
Subject(s)
Androgen Antagonists/administration & dosage , Androgen Antagonists/chemistry , Androgen Receptor Antagonists , Phenyl Ethers/administration & dosage , Phenyl Ethers/chemical synthesis , Sebum/drug effects , Sebum/metabolism , Administration, Topical , Animals , Cell Line, Tumor , Cricetinae , Humans , Male , Mesocricetus , Receptors, Androgen/chemistry , Reproducibility of ResultsABSTRACT
A novel nonsteroidal androgen receptor antagonist, (R)-4-(1-benzyl-4,4-dimethyl-2-oxopyrrolidin-3-yloxy)-2-(trifluoromethyl)benzonitrile (1), for the topical control of sebum production is reported. This compound, which is potent, selective, and efficacious in the clinically validated golden Syrian hamster ear animal model, was designed to be delivered to the pilosebaceous unit, the site of action, preferentially by the follicular route.
Subject(s)
Androgen Receptor Antagonists , Drug Design , Hair Follicle , Nitriles/administration & dosage , Nitriles/pharmacology , Sebum/drug effects , Sebum/metabolism , Administration, Topical , Animals , Chemical Phenomena , Cricetinae , Drug-Related Side Effects and Adverse Reactions , Humans , Male , Mesocricetus , Nitriles/metabolism , Nitriles/pharmacokineticsABSTRACT
A series of substituted 4-aryl-2-trifluoromethylbenzonitrile analogs were evaluated in the human androgen receptor binding and cellular functional assays. Analogs with sufficient in vitro binding and cellular potency (IC(50)<200 nM) were tested in the progesterone receptor binding assay for selectivity and in the Golden Syrian hamster ear model for in vivo efficacy. Within the series, compound 4 e was identified to be the most active analog in vivo (wax ester inhibition=86%).
Subject(s)
Androgen Receptor Antagonists , Fluorine/chemistry , Nitriles/chemistry , Nitriles/pharmacology , Receptors, Androgen/metabolism , Sebum/drug effects , Sebum/metabolism , Humans , Inhibitory Concentration 50 , Methylation , Molecular Structure , Nitriles/chemical synthesis , Structure-Activity RelationshipABSTRACT
A series of amino-pyridines were synthesized and evaluated for androgen antagonist activities. Among these compounds, (R)-(+)-6-[methyl-(1-phenyl-ethyl)-amino]-4-trifluoromethyl-nicotinonitrile was the most active example of this class. This compound displayed potent androgen receptor antagonist activity as well as favorable pharmacokinetic characteristics for a potential topical agent. It also demonstrated remarkable potency for stimulating hair growth in a male C3H mouse model as well as reducing sebum production in the male Syrian hamster ear model.
Subject(s)
Aminopyridines/chemistry , Aminopyridines/pharmacology , Androgen Receptor Antagonists , Hair/drug effects , Hair/growth & development , Sebum/drug effects , Sebum/metabolism , Aminopyridines/chemical synthesis , Animals , Dose-Response Relationship, Drug , Male , Mice , Mice, Inbred C3H , Models, Molecular , Molecular Structure , Receptors, Androgen/metabolism , Structure-Activity RelationshipABSTRACT
Synthesis, pharmacology, and pharmacokinetic profiles of (1R, 2S)-4-(2-cyano-cyclohexyl-oxy)-2-trifluoromethyl-benzonitrile are reported. This compound demonstrated remarkable potency for stimulating hair growth in a male C3H mouse model as well as reducing sebum production in the male Syrian hamster ear model.
Subject(s)
Androgen Antagonists/pharmacology , Hair/growth & development , Hydrocarbons, Fluorinated/pharmacology , Nitriles/pharmacology , Sebum , Animals , Cricetinae , Hydrocarbons, Fluorinated/pharmacokinetics , Male , Mesocricetus , Mice , Models, Molecular , Nitriles/pharmacokineticsABSTRACT
The inhibition of the cytosolic isoenzyme BCAT that is expressed specifically in neuronal tissue is likely to be useful for the treatment of neurodegenerative and other neurological disorders where glutamatergic mechanisms are implicated. Compound 2 exhibited an IC50 of 0.8 microM in the hBCATc assays; it is an active and selective inhibitor. Inhibitor 2 also blocked calcium influx into neuronal cells following inhibition of glutamate uptake, and demonstrated neuroprotective efficacy in vivo. SAR, pharmacology, and the crystal structure of hBCATc with inhibitor 2 are described.
Subject(s)
Benzofurans/chemical synthesis , Benzofurans/therapeutic use , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/therapeutic use , Neurodegenerative Diseases/drug therapy , Sulfonamides/chemical synthesis , Sulfonamides/therapeutic use , Transaminases/antagonists & inhibitors , Animals , Benzofurans/chemistry , Calcium/antagonists & inhibitors , Calcium/metabolism , Cells, Cultured , Crystallography, X-Ray , Drug Design , Drug Evaluation, Preclinical , Enzyme Inhibitors/chemistry , Glutamic Acid/drug effects , Glutamic Acid/metabolism , Humans , In Vitro Techniques , Models, Molecular , Molecular Structure , Neurons/cytology , Neurons/drug effects , Rats , Rats, Inbred Lew , Stereoisomerism , Structure-Activity Relationship , Sulfonamides/chemistryABSTRACT
A series of sulfonamides (1) has been prepared as inhibitors of interleukin-1beta converting enzyme (ICE), also known as caspase 1. These compounds were designed to improve potency by rigidifying the enzyme bound molecule through an intramolecular hydrogen bond. An X-ray crystal structure of a representative member of this series bound to the active site of ICE, confirms the presence of the hydrogen bonding interaction.
Subject(s)
Caspase Inhibitors , Drug Design , Serpins/chemical synthesis , Serpins/pharmacology , Sulfonamides/chemical synthesis , Sulfonamides/pharmacology , Viral Proteins , Binding Sites , Caspase 1/metabolism , Crystallography, X-Ray , Humans , Hydrogen Bonding , Models, Molecular , Molecular Conformation , Molecular Structure , Structure-Activity RelationshipABSTRACT
A novel class of reversible inhibitors of Interleukin-1beta-converting enzyme (ICE, caspase-1) were discovered by iterative structure-based design. Guided by the X-ray crystal structure of analogues 1, 7 and 10 bound to ICE, we have designed a nonpeptide series of small molecule inhibitors. These compounds incorporate an arylsulfonamide moiety which replaces Val-His unit (P3-P2 residues) amino acids of the native substrate. The synthesis of the core structure, structure-activity relationships (SARs), and proposed binding orientation based on molecular modeling studies for this series of ICE inhibitors are described.