ABSTRACT
A novel parallel medicinal chemistry (PMC)-enabled synthesis of 1H-pyrazolo[3,4-d]pyrimidines employing condensation of easily accessible N-pyrazolylamides and nitriles has been developed. The presented studies describe singleton and library enablements that allowed rapid generation of molecular diversity to examine C4 and C6 vectors. This chemistry enabled access to challenging alkyl substituents, expanding the overall chemical space beyond that available via typical C(sp2)-C(sp2) coupling and SNAr transformations. Furthermore, monomer group interconversions allowing the use of larger and more diverse amides and carboxylic acids as precursors to nitriles are discussed.
Subject(s)
Amides/chemistry , Nitriles/chemistry , Pyrazoles/chemistry , Pyrimidines/chemistry , Chemistry, Pharmaceutical , Drug Carriers , Humans , Particle Size , Pyrazoles/chemical synthesis , Pyrimidines/chemical synthesis , Surface PropertiesABSTRACT
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
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
Utilizing structure-based virtual library design and scoring, a novel chimeric series of phosphodiesterase 10A (PDE10A) inhibitors was discovered by synergizing binding site interactions and ADME properties of two chemotypes. Virtual libraries were docked and scored for potential binding ability, followed by visual inspection to prioritize analogs for parallel and directed synthesis. The process yielded highly potent and selective compounds such as 16. New X-ray cocrystal structures enabled rational design of substituents that resulted in the successful optimization of physical properties to produce in vivo activity and to modulate microsomal clearance and permeability.
Subject(s)
Antipsychotic Agents/chemical synthesis , Phosphodiesterase Inhibitors/chemical synthesis , Phosphoric Diester Hydrolases/metabolism , Schizophrenia/drug therapy , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Animals , Antipsychotic Agents/pharmacokinetics , Antipsychotic Agents/pharmacology , Avoidance Learning/drug effects , Binding Sites , Blood-Brain Barrier/metabolism , Corpus Striatum/drug effects , Corpus Striatum/metabolism , Crystallography, X-Ray , Cyclic GMP/metabolism , Databases, Factual , Drug Design , Humans , In Vitro Techniques , Mice , Mice, Knockout , Microsomes, Liver/metabolism , Models, Molecular , Permeability , Phosphodiesterase Inhibitors/pharmacokinetics , Phosphodiesterase Inhibitors/pharmacology , Phosphoric Diester Hydrolases/genetics , Protein Conformation , Structure-Activity RelationshipABSTRACT
Using a combination of parallel and directed synthesis, the discovery of a highly potent and selective series of adenosine A3 agonists was achieved. High aqueous solubility, required for the intended parenteral route of administration, was achieved by the presence of one or two basic amine functional groups.
Subject(s)
Adenosine A3 Receptor Agonists , Adenosine/chemical synthesis , Adenosine/pharmacology , Adenosine/analogs & derivatives , Humans , Molecular Conformation , Solubility , Stereoisomerism , Structure-Activity Relationship , Water/chemistryABSTRACT
Selective adenosine A(3) agonists have potential utility for the prevention of perioperative myocardial ischemic injury. Herein, we report on the discovery and synthesis of compound 7. This amino nucleoside agonist possesses unprecedented levels of selectivity for the human adenosine A(3) receptor.
