ABSTRACT
Aprepitant or its prodrug fosaprepitant, in combination with a corticosteroid and a 5-HT(3) receptor antagonist, are used to prevent chemotherapy-induced nausea and vomiting. This study evaluated the effect of fosaprepitant 150 mg on CYP3A4 metabolism. Fosaprepitant 150 mg has been submitted to regulatory agencies for consideration of approval as a single-day alternative to the 3-day oral aprepitant antiemetic regimen currently marketed. Part 1 of the study evaluated the drug interaction between fosaprepitant 150 mg and oral dexamethasone (8 mg daily for 3 days). Part 2 of the study evaluated the drug interaction between fosaprepitant 150 mg and oral midazolam (2 mg on days 1 and 4). Thirteen subjects were enrolled in part 1 and 10 in part 2. For dexamethasone, fosaprepitant increased the area under the plasma concentration-time curve from 0 to 24 hours by approximately 2.0-fold on days 1 and 2 and to a lesser extent (~1.2-fold) on day 3. Similarly, for midazolam, fosaprepitant increased the area under the plasma concentration-time curve from 0 hours to infinity by approximately 1.8-fold on day 1 but had no effect on midazolam pharmacokinetics on day 4. Fosaprepitant 150 mg is a weak inhibitor of CYP3A4. Oral dexamethasone doses on days 1 and 2 should be reduced by approximately 50% when coadministered with intravenous fosaprepitant 150 mg on day 1.
Subject(s)
Antiemetics/administration & dosage , Antiemetics/pharmacokinetics , Cytochrome P-450 CYP3A Inhibitors , Dexamethasone/pharmacokinetics , Midazolam/pharmacokinetics , Morpholines/administration & dosage , Administration, Oral , Adolescent , Adult , Antiemetics/blood , Aprepitant , Cross-Over Studies , Cytochrome P-450 CYP3A , Dexamethasone/administration & dosage , Dexamethasone/blood , Female , Humans , Injections, Intravenous , Male , Midazolam/administration & dosage , Midazolam/blood , Neurokinin-1 Receptor Antagonists , Young AdultABSTRACT
The optimization of tertiary carbinamine derived inhibitors of BACE1 from its discovery as an unstable lead to low nanomolar cell active compounds is described. Five-membered heterocycles are reported as stable and potency enhancing linkers. In the course of this work, we have discovered a clear trend where the activity of inhibitors at a given assay pH is dependent on pK(a) of the amino group that interacts directly with the catalytic aspartates. The potency of compounds as inhibitors of Alphabeta production in a cell culture assay correlated much better with BACE1 enzyme potency measured at pH 7.5 than at pH 4.5.
Subject(s)
Amines/metabolism , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Aspartic Acid Endopeptidases/antagonists & inhibitors , Aspartic Acid/metabolism , Enzyme Inhibitors/pharmacology , Catalysis , Humans , Models, Molecular , Structure-Activity RelationshipABSTRACT
A high-throughput screen at 100 microM inhibitor concentration for the BACE-1 enzyme revealed a novel spiropiperidine iminohydantoin aspartyl protease inhibitor template. An X-ray cocrystal structure with BACE-1 revealed a novel mode of binding whereby the inhibitor interacts with the catalytic aspartates via bridging water molecules. Using the crystal structure as a guide, potent compounds with good brain penetration were designed.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Imidazolidines/chemical synthesis , Imidazolidines/pharmacology , Piperidines/chemical synthesis , Piperidines/pharmacology , Amyloid Precursor Protein Secretases/chemistry , Amyloid Precursor Protein Secretases/metabolism , Crystallography, X-Ray , Drug Evaluation, Preclinical , Enzyme Inhibitors/chemistry , Hydrogen Bonding , Imidazolidines/chemistry , Models, Molecular , Molecular Structure , Piperidines/chemistry , Structure-Activity RelationshipSubject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Aspartic Acid Endopeptidases/antagonists & inhibitors , Imidazolidines/chemical synthesis , Imidazolidines/pharmacology , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , Amyloid Precursor Protein Secretases/chemistry , Aspartic Acid Endopeptidases/chemistry , Binding Sites , Crystallography, X-Ray , Hydrogen Bonding , Imidazolidines/chemistry , Mass Spectrometry , Models, Molecular , Protease Inhibitors/chemistryABSTRACT
Thrombin-activatable fibrinolysis inhibitor (TAFI) is an important regulator of fibrinolysis, and inhibitors of this enzyme have potential use in antithrombotic and thrombolytic therapy. Appropriately substituted imidazole acetic acids such as 10j were found to be potent inhibitors of activated TAFI and selective versus the related carboxypeptidases CPA, CPN, and CPM but not CPB. Further, 10j accelerated clot lysis in vitro and was shown to be efficacious in a primate model of thrombosis.
