ABSTRACT
We previously observed a cutaneous type IV immune response in nonhuman primates (NHP) with the mGlu5 negative allosteric modulator (NAM) 7. To determine if this adverse event was chemotype- or mechanism-based, we evaluated a distinct series of mGlu5 NAMs. Increasing the sp3 character of high-throughput screening hit 40 afforded a novel morpholinopyrimidone mGlu5 NAM series. Its prototype, (R)-6-neopentyl-2-(pyridin-2-ylmethoxy)-6,7-dihydropyrimido[2,1-c][1,4]oxazin-4(9H)-one (PF-06462894, 8), possessed favorable properties and a predicted low clinical dose (2 mg twice daily). Compound 8 did not show any evidence of immune activation in a mouse drug allergy model. Additionally, plasma samples from toxicology studies confirmed that 8 did not form any reactive metabolites. However, 8 caused the identical microscopic skin lesions in NHPs found with 7, albeit with lower severity. Holistically, this work supports the hypothesis that this unique toxicity may be mechanism-based although additional work is required to confirm this and determine clinical relevance.
Subject(s)
Allosteric Regulation/drug effects , Heterocyclic Compounds, 3-Ring/pharmacology , Heterocyclic Compounds, 3-Ring/pharmacokinetics , Pyridines/pharmacology , Pyridines/pharmacokinetics , Receptor, Metabotropic Glutamate 5/antagonists & inhibitors , Receptor, Metabotropic Glutamate 5/metabolism , Animals , Female , HEK293 Cells , Heterocyclic Compounds, 3-Ring/adverse effects , Heterocyclic Compounds, 3-Ring/chemistry , Humans , Male , Molecular Docking Simulation , Pyridines/adverse effects , Pyridines/chemistry , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
Using structure based drug design, novel aminobenzisoxazoles as coagulation factor IXa inhibitors were designed and synthesized. Highly selective inhibition of FIXa over FXa was demonstrated. Anticoagulation profile of selected compounds was evaluated by aPTT and PT tests. In vitro ADMET and pharmacokinetic (PK) profiles were also evaluated.
Subject(s)
Factor IXa/antagonists & inhibitors , Isoxazoles/chemistry , Animals , Binding Sites , Blood Coagulation/drug effects , Crystallography, X-Ray , Dogs , Drug Design , Drug Evaluation, Preclinical , Factor IXa/metabolism , Half-Life , Humans , Inhibitory Concentration 50 , Isoxazoles/metabolism , Isoxazoles/pharmacology , Molecular Dynamics Simulation , Partial Thromboplastin Time , Protein Structure, Tertiary , Prothrombin Time , Rats , Structure-Activity RelationshipABSTRACT
Using structure based drug design, a novel class of potent coagulation factor IXa (FIXa) inhibitors was designed and synthesized. High selectivity over FXa inhibition was achieved. Selected compounds were evaluated in rat IV/PO pharmacokinetic (PK) studies and demonstrated desirable oral PK profiles. Finally, the pharmacodynamics (PD) of this class of molecules were evaluated in thrombin generation assay (TGA) in Corn Trypsin Inhibitor (CTI) citrated human plasma and demonstrated characteristics of a FIXa inhibitor.
Subject(s)
Drug Design , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Factor IXa/antagonists & inhibitors , Heterocyclic Compounds, 3-Ring/chemistry , Heterocyclic Compounds, 3-Ring/pharmacology , Administration, Oral , Animals , Crystallography, X-Ray , Enzyme Activation/drug effects , Enzyme Inhibitors/chemistry , Heterocyclic Compounds, 3-Ring/chemical synthesis , Humans , Molecular Structure , RatsABSTRACT
Using structure based drug design (SBDD), a novel class of potent coagulation Factor IXa (FIXa) inhibitors was designed and synthesized. High selectivity over FXa inhibition was achieved. Selected compounds demonstrated oral bioavailability in rat IV/PO pharmacokinetic (PK) studies. Finally, the pharmacodynamics (PD) of this class of molecules was evaluated in Thrombin Generation Assay (TGA) in Corn Trypsin Inhibitor (CTI) citrated human plasma and demonstrated characteristics of a FIXa inhibitor.
Subject(s)
Amines/pharmacology , Enzyme Inhibitors/pharmacology , Factor IXa/antagonists & inhibitors , Administration, Oral , Amines/chemical synthesis , Amines/chemistry , Animals , Biological Availability , Crystallography, X-Ray , Dose-Response Relationship, Drug , Drug Design , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Factor IXa/metabolism , Humans , Models, Molecular , Molecular Structure , Rats , Structure-Activity RelationshipABSTRACT
A novel series of pyrazolopyrazines is herein disclosed as mGluR5 negative allosteric modulators (NAMs). Starting from a high-throughput screen (HTS) hit (1), a systematic structure-activity relationship (SAR) study was conducted with a specific focus on balancing pharmacological potency with physicochemical and pharmacokinetic (PK) properties. This effort led to the discovery of 1-methyl-3-(4-methylpyridin-3-yl)-6-(pyridin-2-ylmethoxy)-1H-pyrazolo[3,4-b]pyrazine (PF470, 14) as a highly potent, selective, and orally bioavailable mGluR5 NAM. Compound 14 demonstrated robust efficacy in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-rendered Parkinsonian nonhuman primate model of l-DOPA-induced dyskinesia (PD-LID). However, the progression of 14 to the clinic was terminated because of a potentially mechanism-mediated finding consistent with a delayed-type immune-mediated type IV hypersensitivity in a 90-day NHP regulatory toxicology study.
Subject(s)
Pyrazines/chemical synthesis , Pyrazoles/chemical synthesis , Receptor, Metabotropic Glutamate 5/metabolism , 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine , Administration, Oral , Allosteric Regulation , Animals , Antiparkinson Agents/adverse effects , Biological Availability , Cell Membrane Permeability , Dogs , Dyskinesia, Drug-Induced/drug therapy , HEK293 Cells , Humans , Hypersensitivity, Delayed/chemically induced , Levodopa/adverse effects , Macaca fascicularis , Madin Darby Canine Kidney Cells , Male , Microsomes, Liver/metabolism , Models, Molecular , Parkinson Disease/drug therapy , Parkinson Disease/etiology , Parkinson Disease/physiopathology , Pyrazines/pharmacology , Pyrazines/toxicity , Pyrazoles/pharmacology , Pyrazoles/toxicity , Radioligand Assay , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
A novel potent NMDA-NR2B selective antagonist without the reactive metabolites formation issue was identified. Through this study, a close correlation between reactive metabolites formation and calculated HOMO energies of parent compounds was found.
Subject(s)
Amides/chemistry , Amides/pharmacology , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Receptors, N-Methyl-D-Aspartate/metabolism , Amides/chemical synthesis , Amides/metabolism , Animals , Cell Line , Glutathione/chemistry , Humans , Mice , Molecular Structure , Neurons/drug effects , Neurons/metabolism , Phenol/chemistry , Phenols/chemistry , Structure-Activity RelationshipABSTRACT
(-)-6-[2-[4-(3-Fluorophenyl)-4-hydroxy-1-piperidinyl]-1-hydroxyethyl]-3,4-dihydro-2(1H)-quinolinone was identified as an orally active NR2B-subunit selective N-methyl-d-aspartate (NMDA) receptor antagonist. It has very high selectivity for NR2B subunits containing NMDA receptors versus the HERG-channel inhibition (therapeutic index=4200 vs NR2B binding IC(50)). This compound has improved pharmacokinetic properties compared to the prototype CP-101,606.
Subject(s)
N-Methylaspartate/antagonists & inhibitors , N-Methylaspartate/metabolism , Pain , Piperidines/chemistry , Quinolones/chemistry , Receptors, N-Methyl-D-Aspartate/metabolism , Animals , Cytochrome P-450 CYP2D6/metabolism , Cytochrome P-450 CYP2D6 Inhibitors , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Ether-A-Go-Go Potassium Channels/metabolism , Inhibitory Concentration 50 , Molecular Structure , Pain/drug therapy , Piperidines/pharmacology , Quinolones/pharmacology , Rats , Structure-Activity RelationshipABSTRACT
Novel NR2B antagonists with an amide tether were found by an approach to avoid pharmacophoric similarity to dofetilide. Structure-activity relationship investigation led to N-[cis-4-hydroxy-4-(5-hydroxypyridin-2-yl)cyclohexyl]-3-henylpropanamide as an orally active NR2B-subtype selective N-methyl-D-aspartate (NMDA) receptor antagonist with very weak HERG (human ether-a-go-go related gene) binding (IC(50)> 30 microM). This compound exhibited potent in vivo anti-allodynic activity in the mouse partial sciatic nerve ligation (PSL) model (minimum effective dose=10 mg/kg, po).
