ABSTRACT
Substantial evidence implicates ß-amyloid (Aß) peptides in the etiology of Alzheimer's disease (AD). Aß is produced by the proteolytic cleavage of the amyloid precursor protein by ß- and γ-secretase suggesting that γ-secretase inhibition may provide therapeutic benefit for AD. Although many γ-secretase inhibitors have been shown to be potent at lowering Aß, some have also been shown to have side effects following repeated administration. All of these side effects can be attributed to altered Notch signaling, another γ-secretase substrate. Here we describe the in vivo characterization of the novel γ-secretase inhibitor SCH 697466 in rodents. Although SCH 697466 was effective at lowering Aß, Notch-related side effects in the intestine and thymus were observed following subchronic administration at doses that provided sustained and complete lowering of Aß. However, additional studies revealed that both partial but sustained lowering of Aßand complete but less sustained lowering of Aß were successful approaches for managing Notch-related side effects. Further, changes in several Notch-related biomarkers paralleled the side effect observations. Taken together, these studies demonstrated that, by carefully varying the extent and duration of Aß lowering by γ-secretase inhibitors, it is possible to obtain robust and sustained lowering of Aß without evidence of Notch-related side effects.
ABSTRACT
An investigation is detailed of the structure activity relationships (SAR) of two sulfone side chains of compound (-)-1a (SCH 900229), a potent, PS1-selective γ-secretase inhibitor and clinical candidate for the treatment of Alzheimer's disease. Specifically, 4-CF(3) and 4-Br substituted arylsulfone analogs, (-)-1b and (-)-1c, are equipotent to compound (-)-1a. On the right hand side chain, linker size and terminal substituents of the pendant sulfone group are also investigated.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Benzopyrans/chemical synthesis , Benzopyrans/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Sulfones/chemical synthesis , Sulfones/pharmacology , Benzopyrans/chemistry , Cyclization , Enzyme Activation/drug effects , Humans , Inhibitory Concentration 50 , Molecular Structure , Pyrans/chemical synthesis , Pyrans/chemistry , Pyrans/pharmacology , Structure-Activity Relationship , Sulfones/chemistryABSTRACT
Cyclic hydroxyamidines were designed and validated as isosteric replacements of the amide functionality. Compounds with these structural motifs were found to be metabolically stable and to possess highly desirable pharmacokinetic profiles. These designs were applied in the identification of γ-secretase modulators leading to highly efficacious agents for reduction of central nervous system Aß(42) in various animal models.
Subject(s)
Amidines/chemical synthesis , Amyloid Precursor Protein Secretases/metabolism , Oxadiazoles/chemical synthesis , Oxazines/chemical synthesis , Amidines/pharmacokinetics , Amidines/pharmacology , Amyloid beta-Peptides/metabolism , Animals , Brain/metabolism , Dogs , HEK293 Cells , Humans , Macaca fascicularis , Male , Oxadiazoles/pharmacokinetics , Oxadiazoles/pharmacology , Oxazines/pharmacokinetics , Oxazines/pharmacology , Peptide Fragments/metabolism , Rats , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Accumulation of the ß-amyloid (Aß) peptides is one of the major pathologic hallmarks in the brains of Alzheimer's disease (AD) patients. Aß is generated by sequential proteolytic cleavage of the amyloid precursor protein (APP) catalyzed by ß- and γ-secretases. Inhibition of Aß production by γ-secretase inhibitors (GSIs) is thus being pursued as a target for treatment of AD. In addition to processing APP, γ-secretase also catalyzes proteolytic cleavage of other transmembrane substrates, with the best characterized one being the cell surface receptor Notch. GSIs reduce Aß production in animals and humans but also cause significant side effects because of the inhibition of Notch processing. The development of GSIs that reduce Aß production and have less Notch-mediated side effect liability is therefore an important goal. γ-Secretase is a large membrane protein complex with four components, two of which have multiple isoforms: presenilin (PS1 or PS2), aph-1 (aph-1a or aph-1b), nicastrin, and pen-2. Here we describe the reconstitution of four γ-secretase complexes in Sf9 cells containing PS1--aph-1a, PS1--aph-1b, PS2--aph-1a, and PS2--aph-1b complexes. While PS1--aph-1a, PS1--aph-1b, and PS2--aph-1a complexes displayed robust γ-secretase activity, the reconstituted PS2--aph-1b complex was devoid of detectable γ-secretase activity. γ-Secretase complexes containing PS1 produced a higher proportion of the toxic species Aß42 than γ-secretase complexes containing PS2. Using the reconstitution system, we identified MRK-560 and SCH 1500022 as highly selective inhibitors of PS1 γ-secretase activity. These findings may provide important insights into developing a new generation of γ-secretase inhibitors with improved side effect profiles.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Cyclic S-Oxides/chemistry , Enzyme Inhibitors/chemistry , Heterocyclic Compounds, 4 or More Rings/chemistry , Presenilin-1/chemistry , Presenilin-2/chemistry , Sulfonamides/chemistry , Amyloid Precursor Protein Secretases/chemistry , Amyloid Precursor Protein Secretases/metabolism , Animals , Cells, Cultured , Cyclic S-Oxides/metabolism , Enzyme Inhibitors/metabolism , Heterocyclic Compounds, 4 or More Rings/metabolism , Humans , Membrane Glycoproteins/chemistry , Membrane Glycoproteins/metabolism , Presenilin-1/metabolism , Presenilin-2/metabolism , Protein Isoforms/chemistry , Protein Isoforms/metabolism , Sulfonamides/metabolismABSTRACT
Complex tetracyclic sulfones were designed as gamma-secretase inhibitors and a stereoselective synthesis was achieved. Gamma-secretase activity was seen predominately in the (-) enantiomeric series. Compounds such as 2a and 2b showed remarkable in vitro and in vivo potency.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Protease Inhibitors/chemical synthesis , Sulfones/chemistry , Amyloid beta-Peptides/antagonists & inhibitors , Animals , Drug Design , Hepatocytes/metabolism , Humans , Mice , Stereoisomerism , Structure-Activity Relationship , Sulfones/chemical synthesis , Sulfones/pharmacologyABSTRACT
The design and development of a new class of small 2,6-disubstituted piperidine N-arylsulfonamide gamma-secretase inhibitors is reported. Lowering molecular weight including the use of conformational constraint led to compounds with less CYP 3A4 liability compared to early leads. Compounds active orally in lowering Abeta levels in Tg CRND8 mice were identified as potential treatments for Alzheimer's disease.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Piperidines/chemical synthesis , Piperidines/pharmacology , Sulfonamides/chemical synthesis , Sulfonamides/pharmacology , Administration, Oral , Amyloid beta-Peptides/biosynthesis , Animals , Area Under Curve , Cytochrome P-450 Enzyme System/metabolism , Drug Design , Magnetic Resonance Spectroscopy , Mice , Molecular Conformation , Molecular Weight , Oxidoreductases/metabolismABSTRACT
Development of cis-2,4,6-trisubstituted piperidine N-arylsulfonamides as gamma-secretase inhibitors for the potential treatment of Alzheimer's disease (AD) is reported.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Piperidines/chemical synthesis , Piperidines/pharmacology , Cytochrome P-450 CYP3A/drug effects , Enzyme Inhibitors/chemistry , Humans , Inhibitory Concentration 50 , Molecular Structure , Piperidines/chemistry , Structure-Activity Relationship , Sulfonamides/chemistryABSTRACT
Attachment of the cyclopropylcarbamate group to the piperidine core of gamma-secretase inhibitors leads to a dramatic increase of their in vitro potency. Strategies for subsequent improvement of the in vivo pharmacokinetic profile of the series are discussed. Resulting compounds significantly reduce Abeta levels in TgCRND8 mice after a single PO dosing at 30 mpk.
Subject(s)
Alzheimer Disease/drug therapy , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/therapeutic use , Amyloid beta-Peptides/antagonists & inhibitors , Amyloid beta-Peptides/biosynthesis , Amyloid beta-Protein Precursor/metabolism , Animals , Area Under Curve , Crystallography, X-Ray , Enzyme Inhibitors/pharmacokinetics , Humans , Indicators and Reagents , Magnetic Resonance Spectroscopy , Mice , Mice, Transgenic , Models, Molecular , Molecular Conformation , Rats , Structure-Activity RelationshipABSTRACT
A novel piperidine series of gamma-secretase inhibitors, potentially useful for the treatment of Alzheimer's disease, is disclosed. SAR investigation revealed the requirement for cis-stereochemistry of the substituents attached to the core, which resulted in the chair-like diaxial conformation of the piperidine ring. The series was optimized to provide inhibitors with IC(50)'s in the single-digit nanomolar range. Absolute stereochemistry of the active enantiomer was assigned.
Subject(s)
Alzheimer Disease/drug therapy , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Piperidines/chemistry , Protease Inhibitors/chemistry , Inhibitory Concentration 50 , Piperidines/chemical synthesis , Protease Inhibitors/chemical synthesis , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The development of a novel series of tetrahydroquinoline-derived gamma-secretase inhibitors for the potential treatment of Alzheimer's disease is described.
Subject(s)
Alzheimer Disease/drug therapy , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Protease Inhibitors/chemistry , Quinolines/chemistry , Sulfonamides/chemistry , Humans , Protease Inhibitors/chemical synthesis , Quinolines/chemical synthesis , Structure-Activity Relationship , Sulfonamides/chemical synthesisABSTRACT
Structurally novel thrombin receptor (protease activated receptor 1, PAR-1) antagonists based on the natural product himbacine are described. The prototypical PAR-1 antagonist 55 showed a Ki of 2.7 nM in the binding assay, making it the most potent PAR-1 antagonist reported. 55 was highly active in several functional assays, showed excellent oral bioavailability in rat and monkey models, and showed complete inhibition of agonist-induced ex vivo platelet aggregation in cynomolgus monkeys after oral administration.
Subject(s)
Alkaloids/chemical synthesis , Fibrinolytic Agents/chemical synthesis , Furans/chemical synthesis , Heterocyclic Compounds, 3-Ring/chemical synthesis , Naphthalenes/chemical synthesis , Piperidines/chemical synthesis , Pyridines/chemical synthesis , Receptor, PAR-1/antagonists & inhibitors , Administration, Oral , Alkaloids/chemistry , Alkaloids/pharmacology , Animals , Biological Availability , Blood Platelets/drug effects , Blood Platelets/metabolism , Chromatography, High Pressure Liquid , Fibrinolytic Agents/chemistry , Fibrinolytic Agents/pharmacology , Furans/chemistry , Furans/pharmacology , Heterocyclic Compounds, 3-Ring/chemistry , Heterocyclic Compounds, 3-Ring/pharmacology , Humans , In Vitro Techniques , Macaca fascicularis , Naphthalenes/chemistry , Naphthalenes/pharmacology , Piperidines/chemistry , Piperidines/pharmacology , Platelet Aggregation Inhibitors/chemical synthesis , Platelet Aggregation Inhibitors/chemistry , Platelet Aggregation Inhibitors/pharmacology , Pyridines/chemistry , Pyridines/pharmacology , Radioligand Assay , Rats , Stereoisomerism , Structure-Activity RelationshipABSTRACT
In search of a PDE5 inhibitor for erectile dysfunction, an SAR was developed from a PDE1/PDE5 purine series of leads, which had modest PDE5 potency and poor isozyme selectivity. A compound (41) with PDE5 inhibition and in vivo activity similar to sildenafil was discovered from this effort. In addition, purine 41 demonstrated superior overall PDE isozyme selectivity when compared to the approved PDE5 inhibitors sildenafil, vardenafil, and tadalafil, which may result in a more favorable side-effect profile.
Subject(s)
Erectile Dysfunction/drug therapy , Phosphodiesterase I/metabolism , Phosphodiesterase Inhibitors/chemical synthesis , Phosphodiesterase Inhibitors/therapeutic use , Phosphoric Diester Hydrolases/metabolism , Purines/chemical synthesis , Purines/therapeutic use , 3',5'-Cyclic-GMP Phosphodiesterases , Animals , Cyclic Nucleotide Phosphodiesterases, Type 5 , Humans , Male , Models, Molecular , Molecular Structure , Piperazines/pharmacology , Purines/chemistry , Rats , Sildenafil Citrate , Structure-Activity Relationship , Sulfones , Vasodilator Agents/chemical synthesis , Vasodilator Agents/pharmacology , Vasodilator Agents/therapeutic useABSTRACT
Development of structure-activity relationship of cyclic guanines I lead us to discovery of a potent and selective series of phosphodiesterase 5 inhibitors 52-59 (IC50=1.3-11.0 nM, PDE6/5=116-600).
Subject(s)
3',5'-Cyclic-GMP Phosphodiesterases/antagonists & inhibitors , Drug Delivery Systems/methods , Erectile Dysfunction/drug therapy , Erectile Dysfunction/enzymology , Guanine/chemistry , Phosphodiesterase Inhibitors/chemistry , 3',5'-Cyclic-GMP Phosphodiesterases/metabolism , Cyclic Nucleotide Phosphodiesterases, Type 5 , Guanine/administration & dosage , Humans , Male , Phosphodiesterase Inhibitors/administration & dosage , Phosphodiesterase Inhibitors/therapeutic use , Polycyclic Compounds/administration & dosage , Polycyclic Compounds/chemistry , Structure-Activity RelationshipABSTRACT
We have discovered potent and selective xanthine PDE5 inhibitors. Compound 25 (PDE5 IC(50)=0.6 nM, PDE6/PDE5=101) demonstrated similar functional efficacy and PK profile to Sildenafil (PDE5 IC(50)=3.5 nM, PDE6/PDE5=7).
Subject(s)
Phosphodiesterase Inhibitors/chemical synthesis , Phosphodiesterase Inhibitors/pharmacology , Phosphoric Diester Hydrolases/metabolism , Xanthines/chemical synthesis , Xanthines/pharmacology , 3',5'-Cyclic-GMP Phosphodiesterases , Alkylation , Animals , Area Under Curve , Cyclic Nucleotide Phosphodiesterases, Type 5 , Drug Design , Electric Stimulation , In Vitro Techniques , Male , Muscle Contraction/drug effects , Muscle Relaxation/drug effects , Penis/drug effects , Piperazines/pharmacology , Purines , Rabbits , Sildenafil Citrate , Structure-Activity Relationship , SulfonesABSTRACT
The synthesis and muscarinic binding properties of compounds based on the 1-[4-(4-arylsulfonyl)phenylmethyl]-4-(1-aroyl-4-piperidinyl)-piperazine skeleton are described. For compounds, substituted with appropriately configured methyl groups at the benzylic center and at the piperazine 2-position, high levels of selective, M(2) subtype affinity could be obtained, particularly when the terminal N-aroyl residue was ortho-substituted.
Subject(s)
Piperazines/chemical synthesis , Piperazines/metabolism , Receptors, Muscarinic/metabolism , Binding Sites , Ligands , Molecular Structure , Piperazines/chemistry , Receptor, Muscarinic M1 , Receptor, Muscarinic M2 , Structure-Activity RelationshipABSTRACT
Himbacine (1), a complex piperidine alkaloid isolated from the bark of Australian magnolias, is a promising lead in Alzheimer's disease research due to its potent muscarinic receptor antagonist property. We have described here a highly efficient synthetic strategy that resulted in the total synthesis of himbacine (1) in about 10% overall yield and isohimbacine (1a), an unnatural isomer of himbacine, in 18% overall yield. The total synthesis of himbacine was initially approached using an intramolecular Diels-Alder reaction as the key step to generate intermediate 5 followed by a [3 + 2] cycloaddition with nitrone 4 to produce the isoxazolidine derivative 3. Methylation followed by catalytic reduction of 3 gave 12'-hydroxyhimbacine (20), which, upon dehydration, gave isohimbacine (1a) as the sole product. In an alternative approach, an all-encompassing intramolecular Diels-Alder reaction of an appropriately substituted tetraene derivative 31, which bears the entire latent carbon framework and functional group substitution of himbacine, gave the desired advanced tricyclic intermediate 33, which was readily converted to (+)-himbeline (2) and (+)-himbacine (1).