ABSTRACT
Starting from a rapidly metabolized adamantane 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) inhibitor 22a, a series of E-5-hydroxy-2-adamantamine inhibitors, exemplified by 22d and (+/-)-22f, was discovered. Many of these compounds are potent inhibitors of 11beta-HSD1 and are selective over 11beta-HSD2 for multiple species (human, mouse, and rat), unlike other reported species-selective series. These compounds have good cellular potency and improved microsomal stability. Pharmacokinetic profiling in rodents indicated moderate to large volumes of distribution, short half-lives, and a pharmacokinetic species difference with the greatest exposure measured in rat with 22d. One hour postdose liver, adipose, and brain tissue 11beta-HSD1 inhibition was confirmed with (+/-)-22f in a murine ex vivo assay. Although 5,7-disubstitued-2-adamantamines provided greater stability, a single, E-5-position, polar functional group afforded inhibitors with the best combination of stability, potency, and selectivity. These results indicate that adamantane metabolic stabilization sufficient to obtain short-acting, potent, and selective 11beta-HSD1 inhibitors has been discovered.
Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , Adamantane/analogs & derivatives , Adamantane/chemical synthesis , Piperazines/chemical synthesis , 11-beta-Hydroxysteroid Dehydrogenase Type 1/genetics , Adamantane/pharmacokinetics , Animals , Cell Line , Humans , In Vitro Techniques , Mice , Microsomes, Liver/metabolism , Piperazines/pharmacokinetics , Rats , Stereoisomerism , Structure-Activity Relationship , Tissue DistributionABSTRACT
Potent and selective adamantane sulfone and sulfonamide inhibitors of 11-beta-HSD-1 have been discovered. Selected compounds from these series have robust pharmacokinetic profiles and strongly inhibit liver, fat, and brain HSD1 for extended periods after oral dosing.
Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , Adamantane/analogs & derivatives , Adamantane/chemical synthesis , Adamantane/pharmacology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , 11-beta-Hydroxysteroid Dehydrogenase Type 2/antagonists & inhibitors , Adipose Tissue/enzymology , Animals , Brain/enzymology , Crystallography, X-Ray , Drug Design , Enzyme Inhibitors/pharmacokinetics , Humans , Indicators and Reagents , Liver/enzymology , Mice , Models, Molecular , Structure-Activity RelationshipABSTRACT
A novel class of adamantane ethers 11beta-hydroxysteroid hydrogenase type I inhibitors has been discovered. These compounds have excellent HSD-1 potency and selectivity against HSD-2. The structure-activity relationships, selectivity, metabolism, PK, ex vivo pharmacodynamic data, and an X-ray crystal structure of one of these inhibitors bound to h-HSD-1 are discussed.
Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , Adamantane/analogs & derivatives , Adamantane/pharmacology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , 11-beta-Hydroxysteroid Dehydrogenase Type 1/genetics , Adamantane/chemical synthesis , Alkylation , Animals , Crystallography, X-Ray , Dose-Response Relationship, Drug , Ethers/chemical synthesis , Ethers/pharmacology , Half-Life , Humans , Indicators and Reagents , Mice , Mice, Knockout , Microsomes, Liver/enzymology , Microsomes, Liver/metabolism , Models, MolecularABSTRACT
A series of metabolically stable adamantane amide 11beta-HSD1 inhibitors have been synthesized and biologically evaluated. These compounds exhibit excellent HSD1 potency and HSD2 selectivity and good pharmacokinetic and pharmacodynamic profiles.
Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , Adamantane/chemical synthesis , Adamantane/pharmacology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , 11-beta-Hydroxysteroid Dehydrogenase Type 2/antagonists & inhibitors , Adamantane/chemistry , Animals , Cell Line , Drug Evaluation, Preclinical , Enzyme Activation/drug effects , Enzyme Inhibitors/chemistry , Heterocyclic Compounds/chemical synthesis , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/pharmacology , Humans , In Vitro Techniques , Mice , Microsomes, Liver/drug effects , Microsomes, Liver/enzymology , Molecular Conformation , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A series of metabolically stable butyrolactam 11beta-HSD1 inhibitors have been synthesized and biologically evaluated. These compounds exhibit excellent HSD1 potency and HSD2 selectivity, pharmacokinetic, and pharmacodynamic profiles.
Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , Lactams/pharmacology , Administration, Oral , Animals , Humans , Lactams/administration & dosage , Lactams/chemical synthesis , Lactams/pharmacokinetics , Metabolic Syndrome/drug therapy , MiceABSTRACT
Inhibitors of farnesyltransferase are effective against a variety of tumors in mouse models of cancer. Clinical trials to evaluate these agents in humans are ongoing. In our effort to develop new farnesyltransferase inhibitors, we have discovered a series of aryl tetrahydropyridines that incorporate substituted glycine, phenylalanine and histidine residues. The design, synthesis, SAR and biological properties of these compounds will be discussed.
Subject(s)
Alkyl and Aryl Transferases/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Glycine/analogs & derivatives , Histidine/analogs & derivatives , Phenylalanine/analogs & derivatives , Pyridines/chemical synthesis , Pyridines/pharmacology , Biological Availability , Crystallography, X-Ray , Enzyme Inhibitors/pharmacokinetics , Farnesyltranstransferase , Genes, ras/drug effects , Glycine/pharmacology , Histidine/pharmacology , Models, Molecular , Molecular Conformation , Phenylalanine/pharmacology , Structure-Activity RelationshipABSTRACT
Inhibitors of farnesyltransferase are effective against a variety of tumors in mouse models of cancer. Clinical trials to evaluate these agents in humans are ongoing. In our effort to develop new farnesyltransferase inhibitors, we have discovered bioavailable aryl tetrahydropyridines that are potent in cell culture. The design, synthesis, SAR and biological properties of these compounds will be discussed.
