ABSTRACT
Hydroisoindoline 2 has been previously identified as a potent, brain-penetrant NK1 receptor antagonist with a long duration of action and improved profile of CYP3A4 inhibition and induction compared to aprepitant. However, compound 2 is predicted, based on data in preclinical species, to have a human half-life longer than 40 h and likely to have drug-drug-interactions (DDI), as 2 is a victim of CYP3A4 inhibition caused by its exclusive clearance pathway via CYP3A4 oxidation in humans. We now report 2-[(3aR,4R,5S,7aS)-5-{(1S)-1-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxyethoxy}-4-(2-methylphenyl)octahydro-2H-isoindol-2-yl]-1,3-oxazol-4(5H)-one (3) as a next generation NK1 antagonist that possesses an additional clearance pathway through glucuronidation in addition to that via CYP3A4 oxidation. Compound 3 has a much lower propensity for drug-drug interactions and a reduced estimated human half-life consistent with once daily dosing. In preclinical species, compound 3 has demonstrated potency, brain penetration, and a safety profile similar to 2, as well as excellent pharmacokinetics.
Subject(s)
Isoindoles/chemical synthesis , Neurokinin-1 Receptor Antagonists/chemical synthesis , Oxazoles/chemical synthesis , Cytochrome P-450 CYP3A , Cytochrome P-450 CYP3A Inhibitors , Drug Interactions , Glucuronides/metabolism , Humans , Isoindoles/chemistry , Isoindoles/pharmacokinetics , Isoindoles/pharmacology , Metabolic Clearance Rate , Neurokinin-1 Receptor Antagonists/chemistry , Neurokinin-1 Receptor Antagonists/pharmacokinetics , Neurokinin-1 Receptor Antagonists/pharmacology , Oxazoles/chemistry , Oxazoles/pharmacokinetics , Oxazoles/pharmacology , Peptide Fragments/pharmacology , Substance P/analogs & derivatives , Substance P/pharmacologyABSTRACT
A new class of potent NK(1) receptor antagonists with a tetrahydroindolizinone core has been identified. This series of compounds demonstrated improved functional activities as compared to previously identified 5,5-fused pyrrolidine lead structures. SAR at the 7-position of the tetrahydroindolizinone core is discussed in detail. A number of compounds displayed high NK(1) receptor occupancy at both 1 h and 24 h in a gerbil foot tapping model. Compound 40 has high NK(1) binding affinity, good selectivity for other NK receptors and promising in vivo properties. It also has clean P(450) inhibition and hPXR induction profiles.
Subject(s)
Indolizines/chemistry , Indolizines/pharmacology , Neurokinin-1 Receptor Antagonists , Receptors, Neurokinin-1/metabolism , Animals , Gerbillinae , Humans , Indolizines/pharmacokinetics , Structure-Activity RelationshipABSTRACT
3-[(3aR,4R,5S,7aS)-5-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-4-(4-fluorophenyl)octahydro-2H-isoindol-2-yl]cyclopent-2-en-1-one (17) is a high affinity, brain-penetrant, hydroisoindoline-based neurokinin-1 (NK(1)) receptor antagonist with a long central duration of action in preclinical species and a minimal drug-drug interaction profile. Positron emission tomography (PET) studies in rhesus showed that this compound provides 90% NK(1) receptor blockade in rhesus brain at a plasma level of 67 nM, which is about 10-fold more potent than aprepitant, an NK(1) antagonist marketed for the prevention of chemotherapy-induced and postoperative nausea and vomiting (CINV and PONV). The synthesis of this enantiomerically pure compound containing five stereocenters includes a Diels-Alder condensation, one chiral separation of the cyclohexanol intermediate, an ether formation using a trichloroacetimidate intermediate, and bis-alkylation to form the cyclic amine.
Subject(s)
Brain/metabolism , Isoindoles/metabolism , Isoindoles/pharmacology , Neurokinin-1 Receptor Antagonists , Administration, Oral , Animals , Aprepitant , CHO Cells , Cricetinae , Cricetulus , Drug Interactions , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/metabolism , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/pharmacology , Humans , Inhibitory Concentration 50 , Isoindoles/chemical synthesis , Isoindoles/pharmacokinetics , Macaca mulatta , Morpholines/pharmacology , StereoisomerismABSTRACT
Previous work on human NK(1) antagonists in which the core of the structure is a substituted pyrrolidine has been disclosed. These compounds showed good binding affinity and functional IP activity, however, many did not exhibit the necessary brain penetration for good in vivo activity. The discovery and preparation of a novel 5,5-fused pyrrolidine core is presented in this paper. This scaffold maintains the excellent binding affinity and functional IP activity of the previously reported compounds, but also exhibits excellent brain penetration as observed in a gerbil foot-tapping assay. The determination of the core structural stereochemistry, which eventually led to the final synthesis of a single active diastereomer, is described.
Subject(s)
Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Neurokinin-1 Receptor Antagonists , Pyrroles/chemical synthesis , Pyrroles/pharmacology , Receptors, Neurokinin-1/metabolism , Amides/chemistry , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Epoxy Compounds/chemistry , Humans , Hydroxylation , Methylation , Molecular Structure , Pyrroles/chemistry , Stereoisomerism , Urea/chemistryABSTRACT
The preparation and structure-activity-relationships of novel pyrrolidine-carboxamides and oxadiazoles are described. Compounds in this series were found to be potent hNK(1) antagonists in vitro and efficacious in vivo with minimal interactions with P(450) liver enzymes. Oxadiazole analog 22 was determined to have excellent hNK(1) binding affinity, functional activity, and a good PD response in vivo.
Subject(s)
Alkaloids/pharmacology , Antiviral Agents/pharmacology , Hepatitis B virus/drug effects , Menispermaceae/chemistry , Oxadiazoles/pharmacology , Pyrrolidines/pharmacology , Alkaloids/chemistry , Antiviral Agents/chemistry , Cell Line , Chromatography, Ion Exchange , Hepatitis B Surface Antigens/metabolism , Hepatitis B e Antigens/metabolism , Humans , Magnetic Resonance Spectroscopy , Models, Molecular , Molecular Conformation , Oxadiazoles/chemistry , Pyrrolidines/chemistry , Spectrometry, Mass, Electrospray IonizationABSTRACT
SAR studies on amides, ureas, and vinylogous amides derived from pyrrolidine led to the discovery of several potent hNK(1) antagonists. One particular vinylogous amide (45b) had excellent potency, selectivity, pharmacokinetic profile, and functional activity in vivo. An in vivo rhesus macaque brain receptor occupancy PET study for compound 45b revealed an estimated Occ(90) approximately 300 ng/ml.
Subject(s)
Neurokinin-1 Receptor Antagonists , Pyrrolidines/pharmacology , Administration, Oral , Animals , Biological Availability , Brain/metabolism , Humans , Macaca mulatta , Pyrrolidines/pharmacokinetics , Species SpecificityABSTRACT
A series of 8-azabicyclo[3.2.1]octane amine hNK1 antagonists has been investigated and structure-activity relationships of the benzylamine and 6-exo substituents described. Acidic substituents at C6 give a series of high affinity compounds for hNK1 with selectivity over the hERG channel.
