ABSTRACT
We have identified a series of novel insulin receptor partial agonists (IRPAs) with a potential to mitigate the risk of hypoglycemia associated with the use of insulin as an antidiabetic treatment. These molecules were designed as dimers of native insulin connected via chemical linkers of variable lengths with optional capping groups at the N-terminals of insulin chains. Depending on the structure, the maximal activation level (%Max) varied in the range of â¼20-70% of native insulin, and EC50 values remained in sub-nM range. Studies in minipig and dog demonstrated that IRPAs had sufficient efficacy to normalize plasma glucose levels in diabetes, while providing reduction of hypoglycemia risk. IRPAs had a prolonged duration of action, potentially making them suitable for once-daily dosing. Two lead compounds with %Max values of 30 and 40% relative to native insulin were selected for follow up studies in the clinic.
Subject(s)
Diabetes Mellitus, Type 2 , Hypoglycemia , Animals , Blood Glucose , Diabetes Mellitus, Type 2/drug therapy , Dogs , Hypoglycemia/drug therapy , Hypoglycemic Agents/pharmacology , Hypoglycemic Agents/therapeutic use , Insulin/therapeutic use , Receptor, Insulin , Swine , Swine, Miniature , Therapeutic IndexABSTRACT
The design and synthesis of a new series of tetrahydrobenzisoxazoles as modulators of γ-secretase activity and their structure-activity relationship (SAR) will be detailed. Several compounds are active γ-secretase modulators (GSMs) with good to excellent selectivity for the reduction of Aß42 in the cellular assay. Compound 14a was tested in vivo in a nontransgenic rat model and was found to significantly reduce Aß42 in the CNS compartment compared to vehicle-treated animals (up to 58% reduction of cerebrospinal fluid Aß42 as measured 3 h after an acute oral dosing at 30 mg/kg).
ABSTRACT
Molecular modeling of unbound tricyclic guanine scaffolds indicated that they can serve as effective bioisosteric replacements of xanthines. This notion was further confirmed by a combination of X-ray crystallography and SAR studies, indicating that tricyclic guanine DPP4 inhibitors mimic the binding mode of xanthine inhibitors, exemplified by linagliptin. Realization of the bioisosteric relationship between these scaffolds potentially will lead to a wider application of cyclic guanines as xanthine replacements in drug discovery programs for a variety of biological targets. Newly designed DPP4 inhibitors achieved sub-nanomolar potency range and demonstrated oral activity in vivo in mouse glucose tolerance test.
Subject(s)
Dipeptidyl Peptidase 4/metabolism , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Guanine/pharmacology , Xanthines/pharmacology , Animals , Blood Glucose/drug effects , Crystallography, X-Ray , Dipeptidyl-Peptidase IV Inhibitors/administration & dosage , Dipeptidyl-Peptidase IV Inhibitors/chemistry , Dose-Response Relationship, Drug , Glucose Tolerance Test , Guanine/analogs & derivatives , Guanine/chemistry , Humans , Male , Mice , Mice, Inbred C57BL , Models, Molecular , Molecular Structure , Structure-Activity Relationship , Xanthines/administration & dosage , Xanthines/chemistryABSTRACT
The design, synthesis, SAR, and biological profile of a substituted 4-morpholine sulfonamide series of γ-secretase inhibitors (GSIs) were described. In several cases, the resulting series of GSIs reduced CYP liabilities and improved γ-secretase inhibition activity compared to our previous research series. Selected compounds demonstrated significant reduction of amyloid-ß (Aß) after acute oral dosing in a transgenic animal model of Alzheimer's disease (AD).
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Drug Design , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Morpholines/chemistry , Morpholines/pharmacology , Sulfonamides/chemistry , Alzheimer Disease/drug therapy , Animals , Enzyme Inhibitors/therapeutic use , Female , Male , Mice , Morpholines/therapeutic use , Structure-Activity RelationshipABSTRACT
In the present paper, we described the design, synthesis, SAR, and biological profile of a novel spirocyclic sulfone series of γ-secretase inhibitors (GSIs) related to MRK-560. We utilized an additional spirocyclic ring system to stabilize the active chair conformation of the parent γ-secretase inhibitors. The resulting series is devoid of the CYP2C9 inhibition liability of MRK-560. A few representative analogs were assessed in a nontransgenic animal model of Alzheimer's disease (AD), demonstrating reduction of amyloid-ß (Aß) in the CNS after acute oral dosing. A spirocyclic phosphonate was identified as the optimal ring system for both potency and pharmacokinetics. Compared to GSIs studied in the clinic, representative spirocyclic phosphonate 18a(-) features improved selectivity for the inhibition of the PS-1 isoform of γ-secretase (33-fold vs PS-2), which may alleviate the adverse effect profile of the clinical GSIs.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Drug Discovery/methods , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Alzheimer Disease/drug therapy , Amyloid beta-Peptides/antagonists & inhibitors , Amyloid beta-Peptides/metabolism , Animals , Biological Availability , Central Nervous System/drug effects , Central Nervous System/metabolism , Cytochrome P-450 CYP2C9/metabolism , Cytochrome P-450 Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/pharmacokinetics , HEK293 Cells , Humans , Molecular Conformation , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Sulfonamides/pharmacologyABSTRACT
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
The design of amide and heteroaryl amide isosteres as replacements for the carbamate substructure in previously disclosed 2,6-disubstituted piperidine N-arylsulfonamides is described. In several cases, amides lessened CYP liabilities in this class of gamma-secretase inhibitors. Selected compounds showed significant reduction of Abeta levels upon oral dosing in a transgenic murine model of Alzheimer's disease.
Subject(s)
Amides/chemistry , Amides/pharmacology , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/pharmacology , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Amides/pharmacokinetics , Amyloid beta-Peptides/metabolism , Animals , Carbamates/chemistry , Carbamates/pharmacokinetics , Carbamates/pharmacology , Cytochrome P-450 Enzyme Inhibitors , Heterocyclic Compounds/pharmacokinetics , Mice , Oxadiazoles/chemistry , Oxadiazoles/pharmacokinetics , Oxadiazoles/pharmacology , Piperidines/chemistry , Piperidines/pharmacokinetics , Piperidines/pharmacology , Protease Inhibitors/pharmacokinetics , Rats , Structure-Activity RelationshipABSTRACT
A novel methodology for parallel liquid-phase synthesis of carbamates suitable for the preparation of sterically hindered molecules is disclosed. The alcohols are converted to 4-nitrophenylcarbonates, followed by the reaction with amines. Side product 4-nitrophenol and the unreacted excess amines are scavenged by appropriately chosen cleanup resins, selected among Amberlyst A26 (hydroxide form) and macroporous sulfonic acid (MP-TsOH) or polystyrene isocyanate (PS-NCO) and polystyrene benzaldehyde (PS-PhCHO) resins. As a part of a medicinal chemistry program directed toward finding gamma-secretase inhibitors as prospective drug candidates for Alzheimer's disease, a 6 x 24 library of carbamates was prepared. Out of 144 library members, 133 had a purity for the targeted compound of 80% or better. The prepared compounds were assessed in the gamma-secretase inhibition assay and demonstrated activity with IC 50 values in the range from 1 microM to 5 nM, with the activity of 7 compounds being better than 10 nM.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Carbamates , Combinatorial Chemistry Techniques , Enzyme Inhibitors , Small Molecule Libraries , Amyloid beta-Protein Precursor/biosynthesis , Amyloid beta-Protein Precursor/genetics , Carbamates/chemical synthesis , Carbamates/chemistry , Carbamates/pharmacology , Cell Line , Cell Membrane/drug effects , Cell Membrane/enzymology , Cell Membrane/metabolism , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Humans , Molecular Structure , Mutation , Phase Transition , Small Molecule Libraries/chemical synthesis , Small Molecule Libraries/chemistry , Small Molecule Libraries/pharmacology , Solutions , Structure-Activity RelationshipABSTRACT
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
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).
