ABSTRACT
A series of mechanism-based heteroaryl urea fatty acid amide hydrolase (FAAH) inhibitors with fused bicyclic diamine cores is described. In contrast to compounds built around a piperazine core, most of the fused bicyclic diamine bearing analogs prepared exhibited greater potency against rFAAH than the human enzyme. Several compounds equipotent against both species were identified and profiled in vivo.
Subject(s)
Amidohydrolases/antagonists & inhibitors , Diamines/pharmacology , Enzyme Inhibitors/pharmacology , Urea/pharmacology , Amidohydrolases/metabolism , Animals , Diamines/chemistry , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Molecular Structure , Rats , Structure-Activity Relationship , Urea/analogs & derivatives , Urea/chemistryABSTRACT
The SAR of brain penetration for a series of heteroaryl piperazinyl- and piperadinyl-urea fatty acid amide hydrolase (FAAH) inhibitors is described. Brain/plasma (B/P) ratios ranging from >4:1 to as low as 0.02:1 were obtained through relatively simple structural changes to various regions of the heteroaryl urea scaffold. It was not possible to predict the degree of central nervous system (CNS) penetration from the volumes of distribution (Vd) obtained from pharmacokinetic (PK) experiments as very high Vds did not correlate with high B/P ratios. Similarly, calculated topological polar surface areas (TPSAs) did not consistently correlate with the degree of brain penetration. The lowest B/P ratios were observed for those compounds that were significantly ionized at physiological pH. However, as this class of compounds inhibits the FAAH enzyme through covalent modification, low B/P ratios did not preclude effective central target engagement.
Subject(s)
Amidohydrolases/antagonists & inhibitors , Brain/drug effects , Enzyme Inhibitors/pharmacology , Urea/pharmacology , Amidohydrolases/metabolism , Brain/metabolism , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Molecular Structure , Structure-Activity Relationship , Urea/analogs & derivatives , Urea/chemistryABSTRACT
A series of 1-aryl-2-(((6-aryl)pyrimidin-4-yl)amino)ethanols have been found to be competitive inhibitors of fatty acid amide hydrolase (FAAH). One member of this class, JNJ-40413269, was found to have excellent pharmacokinetic properties, demonstrated robust central target engagement, and was efficacious in a rat model of neuropathic pain.
Subject(s)
Amidohydrolases/antagonists & inhibitors , Amino Alcohols/chemistry , Analgesics/chemistry , Enzyme Inhibitors/chemistry , Pyrimidines/chemistry , Amidohydrolases/metabolism , Amino Alcohols/pharmacokinetics , Amino Alcohols/therapeutic use , Analgesics/pharmacokinetics , Analgesics/therapeutic use , Animals , Binding Sites , Brain/metabolism , Catalytic Domain , Disease Models, Animal , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/therapeutic use , Half-Life , Humans , Molecular Docking Simulation , Neuralgia/drug therapy , Protein Binding , Pyrimidines/pharmacokinetics , Pyrimidines/therapeutic use , Rats , Structure-Activity RelationshipABSTRACT
A series of mechanism based heteroaryl urea fatty acid amide hydrolase (FAAH) inhibitors with spirocyclic diamine cores is described. A potent member of this class, (37), was found to inhibit FAAH centrally, elevate the brain levels of three fatty acid ethanolamides [FAAs: anandamide (AEA), oleoyl ethanolamide (OEA) and palmitoyl ethanolamide (PEA)], and was moderately efficacious in a rat model of neuropathic pain.
Subject(s)
Amidohydrolases/antagonists & inhibitors , Azetidines/chemistry , Azetidines/pharmacology , Diamines/chemical synthesis , Heterocyclic Compounds/chemical synthesis , Spiro Compounds/chemical synthesis , Urea/analogs & derivatives , Administration, Oral , Animals , Azetidines/pharmacokinetics , Brain/enzymology , Brain/metabolism , Cyclization , Diamines/chemistry , Diamines/pharmacology , Enzyme Activation/drug effects , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/pharmacology , Molecular Structure , Rats , Spiro Compounds/chemistry , Spiro Compounds/pharmacology , Urea/chemistry , Urea/pharmacokinetics , Urea/pharmacologyABSTRACT
The structure-activity relationships for a series of heteroaryl urea inhibitors of fatty acid amide hydrolase (FAAH) are described. Members of this class of inhibitors have been shown to inactivate FAAH by covalent modification of an active site serine with subsequent release of an aromatic amine from the urea electrophile. Systematic Ames II testing guided the optimization of urea substituents by defining the structure-mutagenicity relationships for the released aromatic amine metabolites. Potent FAAH inhibitors were identified having heteroaryl amine leaving groups that were non-mutagenic in the Ames II assay.
Subject(s)
Amidohydrolases/antagonists & inhibitors , Amines/metabolism , Enzyme Inhibitors/pharmacology , Mixed Function Oxygenases/metabolism , Mutagens/metabolism , Mutagens/pharmacology , Urea/pharmacology , Amidohydrolases/metabolism , Animals , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Molecular Structure , Mutagenicity Tests , Rats , Structure-Activity Relationship , Urea/analogs & derivatives , Urea/chemistryABSTRACT
The discovery of 1,3,8-triazaspiro[4.5]decane-2,4-diones (spirohydantoins) as a structural class of pan-inhibitors of the prolyl hydroxylase (PHD) family of enzymes for the treatment of anemia is described. The initial hit class, spirooxindoles, was identified through affinity selection mass spectrometry (AS-MS) and optimized for PHD2 inhibition and optimal PK/PD profile (short-acting PHDi inhibitors). 1,3,8-Triazaspiro[4.5]decane-2,4-diones (spirohydantoins) were optimized as an advanced lead class derived from the original spiroindole hit. A new set of general conditions for C-N coupling, developed using a high-throughput experimentation (HTE) technique, enabled a full SAR analysis of the spirohydantoins. This rapid and directed SAR exploration has resulted in the first reported examples of hydantoin derivatives with good PK in preclinical species. Potassium channel off-target activity (hERG) was successfully eliminated through the systematic introduction of acidic functionality to the molecular structure. Undesired upregulation of alanine aminotransferese (ALT) liver enzymes was mitigated and a robust on-/off-target margin was achieved. Spirohydantoins represent a class of highly efficacious, short-acting PHD1-3 inhibitors causing a robust erythropoietin (EPO) upregulation in vivo in multiple preclinical species. This profile deems spirohydantoins as attractive short-acting PHDi inhibitors with the potential for treatment of anemia.
Subject(s)
Anemia/drug therapy , Aza Compounds/chemical synthesis , Hydantoins/chemical synthesis , Hypoxia-Inducible Factor 1/metabolism , Procollagen-Proline Dioxygenase/antagonists & inhibitors , Spiro Compounds/chemical synthesis , Animals , Aza Compounds/pharmacokinetics , Aza Compounds/pharmacology , Dogs , ERG1 Potassium Channel , Erythropoietin/biosynthesis , Ether-A-Go-Go Potassium Channels/metabolism , High-Throughput Screening Assays , Humans , Hydantoins/pharmacokinetics , Hydantoins/pharmacology , Hypoxia-Inducible Factor-Proline Dioxygenases , Indoles/chemical synthesis , Indoles/pharmacokinetics , Indoles/pharmacology , Liver/drug effects , Liver/enzymology , Macaca mulatta , Mass Spectrometry , Mice , Mice, Inbred C57BL , Protein Binding , Rats , Spiro Compounds/pharmacokinetics , Spiro Compounds/pharmacology , Structure-Activity Relationship , Up-RegulationABSTRACT
JP4-039 is a novel nitroxide conjugate capable of crossing lipid bilayer membranes and scavenging reactive oxygen species (ROS). An efficient and scalable one-pot hydrozirconation-transmetalation-imine addition methodology has been developed for its asymmetric preparation. Furthermore, this versatile methodology allows for the synthesis of cyclopropyl and fluorinated analogs of the parent lead structure.