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2.
J Med Chem ; 61(3): 1001-1018, 2018 02 08.
Article in English | MEDLINE | ID: mdl-29293004

ABSTRACT

Computational modeling was used to direct the synthesis of analogs of previously reported phosphodiesterase 2A (PDE2A) inhibitor 1 with an imidazotriazine core to yield compounds of significantly enhanced potency. The analog PF-05180999 (30) was subsequently identified as a preclinical candidate targeting cognitive impairment associated with schizophrenia. Compound 30 demonstrated potent binding to PDE2A in brain tissue, dose responsive mouse brain cGMP increases, and reversal of N-methyl-d-aspartate (NMDA) antagonist-induced (MK-801, ketamine) effects in electrophysiology and working memory models in rats. Preclinical pharmacokinetics revealed unbound brain/unbound plasma levels approaching unity and good oral bioavailability resulting in an average concentration at steady state (Cav,ss) predicted human dose of 30 mg once daily (q.d.). Modeling of a modified release formulation suggested that 25 mg twice daily (b.i.d.) could maintain plasma levels of 30 at or above targeted efficacious plasma levels for 24 h, which became part of the human clinical plan.


Subject(s)
Brain/drug effects , Brain/metabolism , Cyclic Nucleotide Phosphodiesterases, Type 2/antagonists & inhibitors , Drug Discovery , Enzyme Inhibitors/metabolism , Enzyme Inhibitors/pharmacology , Animals , Biological Availability , Brain/physiology , Cyclic Nucleotide Phosphodiesterases, Type 2/chemistry , Cyclic Nucleotide Phosphodiesterases, Type 2/metabolism , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacokinetics , Humans , Imidazoles/chemistry , Imidazoles/metabolism , Imidazoles/pharmacokinetics , Imidazoles/pharmacology , Inhibitory Concentration 50 , Memory, Short-Term/drug effects , Molecular Docking Simulation , Protein Conformation
3.
J Med Chem ; 60(15): 6649-6663, 2017 08 10.
Article in English | MEDLINE | ID: mdl-28598634

ABSTRACT

Recent data demonstrated that activation of the muscarinic M1 receptor by a subtype-selective positive allosteric modulator (PAM) contributes to the gastrointestinal (GI) and cardiovascular (CV) cholinergic adverse events (AEs) previously attributed to M2 and M3 activation. These studies were conducted using PAMs that also exhibited allosteric agonist activity, leaving open the possibility that direct activation by allosteric agonism, rather than allosteric modulation, could be responsible for the adverse effects. This article describes the design and synthesis of lactam-derived M1 PAMs that address this hypothesis. The lead molecule from this series, compound 1 (PF-06827443), is a potent, low-clearance, orally bioavailable, and CNS-penetrant M1-selective PAM with minimal agonist activity. Compound 1 was tested in dose escalation studies in rats and dogs and was found to induce cholinergic AEs and convulsion at therapeutic indices similar to previous compounds with more agonist activity. These findings provide preliminary evidence that positive allosteric modulation of M1 is sufficient to elicit cholinergic AEs.


Subject(s)
Isoindoles/pharmacology , Lactams/pharmacology , Oxazoles/pharmacology , Receptor, Muscarinic M1/agonists , Seizures/chemically induced , Allosteric Regulation , Amphetamine/pharmacology , Animals , Ataxia/chemically induced , Diarrhea/chemically induced , Dogs , Donepezil , Drug Design , Female , Humans , Indans/pharmacology , Isoindoles/administration & dosage , Isoindoles/chemical synthesis , Isoindoles/toxicity , Lactams/administration & dosage , Lactams/chemical synthesis , Lactams/toxicity , Male , Mice, Inbred C57BL , Microsomes, Liver/metabolism , Oxazoles/administration & dosage , Oxazoles/chemical synthesis , Oxazoles/toxicity , Piperidines/pharmacology , Rats, Wistar , Receptor, Muscarinic M1/antagonists & inhibitors , Scopolamine/pharmacology , Structure-Activity Relationship , Sulfonamides/pharmacology , Thiadiazoles/pharmacology , Vomiting/chemically induced
4.
J Med Chem ; 60(13): 5673-5698, 2017 07 13.
Article in English | MEDLINE | ID: mdl-28574706

ABSTRACT

Phosphodiesterase 2A (PDE2A) inhibitors have been reported to demonstrate in vivo activity in preclinical models of cognition. To more fully explore the biology of PDE2A inhibition, we sought to identify potent PDE2A inhibitors with improved brain penetration as compared to current literature compounds. Applying estimated human dose calculations while simultaneously leveraging synthetically enabled chemistry and structure-based drug design has resulted in a highly potent, selective, brain penetrant compound 71 (PF-05085727) that effects in vivo biochemical changes commensurate with PDE2A inhibition along with behavioral and electrophysiological reversal of the effects of NMDA antagonists in rodents. This data supports the ability of PDE2A inhibitors to potentiate NMDA signaling and their further development for clinical cognition indications.


Subject(s)
Cyclic Nucleotide Phosphodiesterases, Type 2/antagonists & inhibitors , Drug Design , Phosphodiesterase Inhibitors/chemistry , Phosphodiesterase Inhibitors/pharmacology , Animals , Brain/drug effects , Brain/metabolism , Crystallography, X-Ray , Cyclic Nucleotide Phosphodiesterases, Type 2/chemistry , Cyclic Nucleotide Phosphodiesterases, Type 2/metabolism , Dogs , Haplorhini , Humans , Mice , Molecular Docking Simulation , Phosphodiesterase Inhibitors/administration & dosage , Phosphodiesterase Inhibitors/pharmacokinetics , Rats
5.
Mol Pharmacol ; 90(3): 177-87, 2016 09.
Article in English | MEDLINE | ID: mdl-27382013

ABSTRACT

Selective activation of the M1 muscarinic acetylcholine receptor (mAChR) via a positive allosteric modulator (PAM) is a new approach for the treatment of the cognitive impairments associated with schizophrenia and Alzheimer's disease. Herein, we describe the characterization of an M1 PAM radioligand, 8-((1S,2S)-2-hydroxycyclohexyl)-5-((6-(methyl-t3)pyridin-3-yl)methyl)-8,9-dihydro-7H-pyrrolo[3,4-hour]quinolin-7-one ([(3)H]PT-1284), as a tool for characterizing the M1 allosteric binding site, as well as profiling novel M1 PAMs. 8-((1S,2S)-2-Hydroxycyclohexyl)-5-((6-methylpyridin-3-yl)methyl)-8,9-dihydro-7H-pyrrolo[3,4-hour]quinolin-7-one (PT-1284 ( 1: )) was shown to potentiate acetylcholine (ACh) in an M1 fluorometric imaging plate reader (FLIPR) functional assay (EC50, 36 nM) and carbachol in a hippocampal slice electrophysiology assay (EC50, 165 nM). PT-1284 ( 1: ) also reduced the concentration of ACh required to inhibit [(3)H]N-methylscopolamine ([(3)H]NMS) binding to M1, left-shifting the ACh Ki approximately 19-fold at 10 µM. Saturation analysis of a human M1 mAChR stable cell line showed that [(3)H]PT-1284 bound to M1 mAChR in the presence of 1 mM ACh with Kd, 4.23 nM, and saturable binding capacity (Bmax), 6.38 pmol/mg protein. M1 selective PAMs were shown to inhibit [(3)H]PT-1284 binding in a concentration-responsive manner, whereas M1 allosteric and orthosteric agonists showed weak affinity (>30 µM). A strong positive correlation (R(2) = 0.86) was found to exist between affinity values generated for nineteen M1 PAMs in the [(3)H]PT-1284 binding assay and the EC50 values of these ligands in a FLIPR functional potentiation assay. These data indicate that there is a strong positive correlation between M1 PAM binding affinity and functional activity, and that [(3)H]PT-1284 can serve as a tool for pharmacological investigation of M1 mAChR PAMs.


Subject(s)
Isoindoles/metabolism , Pyridines/metabolism , Radioligand Assay , Receptor, Muscarinic M1/metabolism , Acetylcholine , Allosteric Regulation , Animals , Autoradiography , CHO Cells , Cricetinae , Cricetulus , Electrophysiological Phenomena , Fluorometry , HEK293 Cells , Hippocampus/physiology , Humans , Kinetics , Male , Membranes/metabolism , N-Methylscopolamine/metabolism , Positron-Emission Tomography , Rats, Sprague-Dawley
6.
J Med Chem ; 59(13): 6313-28, 2016 07 14.
Article in English | MEDLINE | ID: mdl-27275946

ABSTRACT

It is hypothesized that selective muscarinic M1 subtype activation could be a strategy to provide cognitive benefits to schizophrenia and Alzheimer's disease patients while minimizing the cholinergic side effects observed with nonselective muscarinic orthosteric agonists. Selective activation of M1 with a positive allosteric modulator (PAM) has emerged as a new approach to achieve selective M1 activation. This manuscript describes the development of a series of M1-selective pyridone and pyridine amides and their key pharmacophores. Compound 38 (PF-06767832) is a high quality M1 selective PAM that has well-aligned physicochemical properties, good brain penetration and pharmacokinetic properties. Extensive safety profiling suggested that despite being devoid of mAChR M2/M3 subtype activity, compound 38 still carries gastrointestinal and cardiovascular side effects. These data provide strong evidence that M1 activation contributes to the cholinergic liabilities that were previously attributed to activation of the M2 and M3 receptors.


Subject(s)
Drug Discovery , Picolinic Acids/pharmacology , Receptor, Muscarinic M1/agonists , Thiazoles/pharmacology , Animals , Dose-Response Relationship, Drug , Female , Male , Mice , Models, Molecular , Molecular Structure , Picolinic Acids/chemical synthesis , Picolinic Acids/chemistry , Rats , Receptor, Muscarinic M1/metabolism , Structure-Activity Relationship , Thiazoles/chemical synthesis , Thiazoles/chemistry
7.
Bioorg Med Chem Lett ; 26(2): 650-655, 2016 Jan 15.
Article in English | MEDLINE | ID: mdl-26631313

ABSTRACT

Selective activation of the M1 receptor via a positive allosteric modulator (PAM) is a new approach for the treatment of the cognitive impairments associated with schizophrenia and Alzheimer's disease. A novel series of azaindole amides and their key pharmacophore elements are described. The nitrogen of the azaindole core is a key design element as it forms an intramolecular hydrogen bond with the amide N-H thus reinforcing the bioactive conformation predicted by published SAR and our homology model. Representative compound 25 is a potent and selective M1 PAM that has well aligned physicochemical properties, adequate brain penetration and pharmacokinetic (PK) properties, and is active in vivo. These favorable properties indicate that this series possesses suitable qualities for further development and studies.


Subject(s)
Allosteric Regulation/drug effects , Amides/chemistry , Amides/pharmacology , Indoles/chemistry , Indoles/pharmacology , Receptor, Muscarinic M1/metabolism , Amides/pharmacokinetics , Animals , Drug Design , Humans , Hydrogen Bonding , Indoles/pharmacokinetics , Mice , Molecular Docking Simulation , Receptor, Muscarinic M1/agonists
8.
Org Lett ; 17(23): 5760-3, 2015 Dec 04.
Article in English | MEDLINE | ID: mdl-26584509

ABSTRACT

A method for chemoselective carbonyl ylide formation utilizing the Rh(II) catalyzed decomposition of electronically differentiated diazo malonates is disclosed. Treatment of ethyl, trifluoro ethyl diazo malonate with a Rh(II) catalyst selectively forms a carbonyl ylide from the relatively electron rich ethyl ester. This carbonyl ylide can be trapped by various alkynes giving highly functionalized oxabicyclic compounds in a chemo-, regio-, and diastereoselective fashion.


Subject(s)
Alkynes/chemistry , Malonates/chemistry , Catalysis , Cyclization , Esters , Molecular Structure , Rhodium/chemistry , Stereoisomerism
9.
J Org Chem ; 78(6): 2661-9, 2013 Mar 15.
Article in English | MEDLINE | ID: mdl-23438191

ABSTRACT

A stereoselective synthesis of spiropiperidine compounds, exemplified by compound 1, was developed, which was based upon the late stage N-arylation of a 1,8-diazaspiro[4.5]dec-3-en-2-one pharmacophore. Previously, compound 1 was prepared in low overall yield from piperidinone 2 via the Strecker reaction. A new route was developed, which employed the stereospecific Corey-Link reaction of an enantiomerically pure trichloromethylcarbinol to give a template compound amenable to late stage N-arylation.


Subject(s)
Aspartic Acid Endopeptidases/antagonists & inhibitors , Aspartic Acid Endopeptidases/chemistry , Aza Compounds/chemical synthesis , Methanol/chemistry , Piperidines/chemical synthesis , Spiro Compounds/chemical synthesis , Aza Compounds/chemistry , Magnetic Resonance Spectroscopy , Molecular Structure , Piperidines/chemistry , Protease Inhibitors , Spiro Compounds/chemistry , Stereoisomerism , Structure-Activity Relationship
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