ABSTRACT
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 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
3-Hydroxyquinolin-2(1H)-one (2) was discovered by high throughput screening in a functional assay to be a potent inhibitor of human DAAO, and its binding affinity was confirmed in a Biacore assay. Cocrystallization of 2 with the human DAAO enzyme defined the binding site and guided the design of new analogues. The SAR, pharmacokinetics, brain exposure, and effects on cerebellum D-serine are described. Subsequent evaluation against the rat DAAO enzyme revealed a divergent SAR versus the human enzyme and may explain the high exposures of drug necessary to achieve significant changes in rat or mouse cerebellum D-serine.
Subject(s)
D-Amino-Acid Oxidase/antagonists & inhibitors , Hydroxyquinolines/pharmacology , Hydroxyquinolines/pharmacokinetics , Animals , Cerebellum/metabolism , Crystallography, X-Ray , Drug Discovery , Drug Evaluation, Preclinical , Humans , Hydroxyquinolines/chemical synthesis , Male , Mice , Rats , Rats, Sprague-Dawley , Serine/metabolism , Structure-Activity RelationshipABSTRACT
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
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
To understand drug delivery to the sebum filled hair and sebaceous follicles, it is essential to use an artificial sebum as a surrogate of the human sebum for the investigation of drug transport properties. Artificial sebum L was developed in-house based on the chemical similarity to human sebum. The partition and diffusion of model compounds (ethyl 4-hydroxybenzoate, butyl 4-hydroxybenzoate, and hexyl 4-hydroxybenzoate) were measured in human sebum, hamster ear and body sebum (a commonly used animal model), and four representative artificial sebum samples (N, S, F, and L) in which artificial sebums, N, S and F were selected based on the available literature. DSC and NMR studies were also conducted on all sebums to compare their melting properties and chemical compositions. In vitro studies show that the partition coefficients of the three model compounds in artificial sebum L were similar to that of human sebum, whereas the hamster ear and body sebum, and other three artificial sebum samples were different from that of human sebum. Additionally, the in vitro sebum flux (microg/(cm(2)min) of three model compounds through artificial sebum L was closer to that of human sebum when compared with the other three artificial sebum (N, S and F), hamster body and hamster ear sebum. The results of this study indicate that the artificial sebum L could be used as an alternative to human sebum, as the physicochemical properties of this artificial sebum is relatively similar to human sebum.
Subject(s)
Models, Biological , Sebum/chemistry , Administration, Cutaneous , Animals , Biological Transport , Calorimetry, Differential Scanning , Chromatography, High Pressure Liquid , Cricetinae , Drug Delivery Systems , Hair Follicle/metabolism , Humans , Magnetic Resonance Spectroscopy , Sebum/metabolism , Species SpecificityABSTRACT
4-((1 R,2 R)-2-Hydroxycyclohexyl)-2(trifluoromethyl)benzonitrile [PF-0998425, (-)- 6a] is a novel, nonsteroidal androgen receptor antagonist for sebum control and treatment of androgenetic alopecia. It is potent, selective, and active in vivo. The compound is rapidly metabolized systemically, thereby reducing the risk of unwanted systemic side effects due to its primary pharmacology. (-)- 6a was tested negative in the 3T3 NRU assay, validating our rationale that reduction of conjugation might reduce potential phototoxicity.
Subject(s)
Androgen Receptor Antagonists , Cyclohexanols/chemical synthesis , Cyclohexanols/pharmacology , Nitriles/chemical synthesis , Nitriles/pharmacology , Photosensitizing Agents/chemical synthesis , Photosensitizing Agents/pharmacology , Skin , Crystallography, X-Ray , Cyclohexanols/chemistry , Drug Design , Ligands , Models, Molecular , Molecular Structure , Nitriles/chemistry , Photosensitizing Agents/chemistry , Receptors, Androgen/chemistry , Receptors, Androgen/metabolism , Skin/drug effects , Skin/metabolism , Steroids/chemistry , 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
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
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.
