159 results about "Gamma secretase" patented technology

The present invention relates to compositions and methods to treat diseases or condition with an α7 nAChR full agonist and an inhibitor of cholinesterase, and or beta secretase and or gamma secretase.

Disclosed are compounds of the formula

or a pharmaceutically acceptable salt or solvate thereof, wherein

• [0001]
  • R¹ is
  [0002]
  • R is —C(O)—N(R²⁷)(R²⁸) or

and the remaining variables are as defined in the specification. Also disclosed are pharmaceutical compositions comprising the compounds of formula I. Also disclosed are methods of treating cognitive or neurodegenerative diseases such as Alzheimer's disease. Also disclosed are pharmaceutical compositions and methods of treating cognitive or neurodegenerative diseases comprising the compounds of formula I in combination with a β-secretase inhibitor other than those of formula I, an HMG-CoA reductase inhibitor, a gamma-secretase inhibitor, a non-steroidal anti-inflammatory agent, an N-methyl-D-aspartate receptor antagonist, a cholinesterase inhibitor or an anti-amyloid antibody.

Angiogenesis may be initiated or increased through the use of gamma-secretase inhibitors. The gamma-secretase inhibitor can be a dipeptide class, sulfonamide class, transition state mimic class, benzodiazepine class, or benzocaprolactam class gamma secretase inhibitor. Methods for initiating and increasing angiogenesis are used for disease prevention and treatment as well as for generating research models.

Disclosed are novel compounds of the formula

or a pharmaceutically acceptable salt or solvate thereof, wherein

• • R¹, R², R³, n and X are as defined in the specification. Also disclosed are pharmaceutical compositions comprising the compounds of formula I. Also disclosed are methods of treating cognitive or neurodegenerative diseases such as Alzheimer's disease. Also disclosed are methods of treating a cognitive or neurodegenerative disease comprising administering to a patient I need of such treatment a combination of at least one compound of formula I and at least one compound selected from the group consisting of β-secretase inhibitors other than those of formula I, HMG-CoA reductase inhibitors, gamma-secretase inhibitors, non-steroidal anti-inflammatory agents, N-methyl-D-aspartate receptor antagonists, cholinesterase inhibitors and anti-amyloid antibodies.

This invention provides novel compounds that are modulators of gamma secretase. The compounds have the formula

Also disclosed are methods of modulating gamma secretase activity and methods of treating Alzheimer's Disease using the compounds of formula (I).

The invention provides assays and methods for determining whether a compound inhibits gamma secretase in a substrate specific manner. The invention provides an isolated cell wherein the cell stably expresses APP and at least one gamma secretase substrate other than APP. The invention provides assays and methods comprising contacting a cell with gamma secretase and detecting production of Abeta, detecting production of intracellular domain (ICD), and detecting a signal from a reporter gene under transcriptional control of the ICD. The invention also provides compounds that inhibit gamma secretase, pharmaceutical compositions comprising such compounds, and methods of treating Alzheimer's disease using such compounds.

The invention provides assays and methods for determining the substrate specificity of gamma secretase inhibitors and for identifying substrate-selective (and substrate isoform-selective) inhibitors of gamma secretase. The invention provides assays and methods for determining whether a compound inhibits gamma secretase in a site specific or substrate specific manner. The invention provides isolated polypeptide sequences comprising modified gamma secretase substrates, and polynucleotide sequences encoding the polypeptide sequences. The invention also provides compounds that inhibit gamma secretase, pharmaceutical compositions comprising such compounds, and methods of treating Alzheimer's disease using such compounds.

Compounds and pharmaceutically acceptable salts of the compounds are disclosed, wherein the compounds have the structure of Formula (I) as defined in the specification. Corresponding pharmaceutical compositions, methods of treatment, methods of synthesis, and intermediates are also disclosed.

The present invention is concerned with novel substituted benzoxazole, benzimidazole, oxazolopyridine and imidazopyridine derivatives of Formula (I)

wherein R¹, R², R³, R⁴, X, A¹, A², A³, A⁴, Y¹, Y², Y³ and Z have the meaning defined in the claims. The compounds according to the present invention are useful as gamma secretase modulators. The invention further relates to processes for preparing such novel compounds, pharmaceutical compositions comprising said compounds as an active ingredient as well as the use of said compounds as a medicament.

The invention relates to the identification and use of gene expression profiles with clinical relevance to the treatment of cellular proliferative disorders, especially those mediated by aberrant Notch signaling using a Notch signaling inhibitor. In particular, the invention provides the identities of genes, whose individual or cumulative expression patterns may be useful in various assays. The gene expression profiles, whether embodied in nucleic acid expression, protein expression, or other expression formats, may be used to select subjects afflicted with a Notch mediated cancer who will likely respond to treatment with a gamma-secretase inhibitor or another Notch inhibiting agent. The same markers may be used in the classification of patients being treated with other Notch inhibitors. The methods may further comprise providing diagnostic, prognostic, or predictive information based on the classifying step. The methods may further comprise selecting a treatment based on the classifying step.

This invention provides novel compounds that are modulators of gamma secretase. The compounds have the formula (I) wherein R² is a fused bicyclic ring of the formula (II). Also disclosed are methods of modulating gamma secretase activity and methods of treating Alzheimer's disease using the compounds of formula (I).

In accordance with the present invention, it has been discovered that compounds which modulate the γ-secretase enzyme to make more of the shorter, less toxic and less aggregation-prone Aβ peptides (such as Aβ37 and Aβ38), while making less of the longer and more toxic and aggregation-prone AB peptides (such as AB40 and AB42) are useful as gamma-secretase modulators. In addition, these GSM compounds have further been discovered to have the selective property of modulating the formation of various AB peptides, while not inhibiting the overall activity of the γ-secretase enzyme. Thus, such compounds do not impede other critical functions of the γ-secretase enzyme, such as generating fragments from Notch that appear to control gene expression and cell differentiation. Therefore, in accordance with the present invention, there are provided screening assays useful for determining whether test compounds have GSM activity; accordingly, invention assays facilitate the identification of new gamma-secretase modulators. Such screening assays can be performed in a variety of ways, e.g., by assessing whether test compounds: lower the level of Aβ42 peptide, increase the level of Aβ37 and/or Aβ38 peptides, have substantially no effect on the processing of other γ-secretase substrates, and/or interact with at least one component of the γ-secretase complex. Also provided in accordance with the present invention are compounds having gamma-secretase modulatory activity as identified by any of the methods described herein; methods for producing formulations useful for modulating gamma-secretase activity, as well as the resulting formulations; methods for modulating gamma-secretase activity employing compounds identified according to invention methods and/or invention formulations, and the like.

Methods are provided for treating and preventing renal disease in a subject by administering a gamma secretase inhibitor or a Notch pathway inhibitor to the subject.

The present invention is directed to a novel trifluoromethylsulfonamide derivative which inhibits the processing of APP by the putative γ-secretase and thus is useful in the treatment or prevention of Alzheimer's disease. This compound possesses favorable pharmacokinetic properties in higher species (rhesus) and thus can be dosed on an intermittent dosing regiment (e.g., once weekly). When dosed on such a regiment the compound exhibits significant and continuous Aβ lowering without the manifestation of Notch associated gastrointestinal toxicity for extended periods, e.g., 7 days. Pharmaceutical compositions and methods of use are also included.

The present invention is concerned with substituted bicyclic heterocyclic compounds of Formula (I)

wherein Het¹, Het², A¹, A², A³ and A⁴ have the meaning defined in the claims. The compounds according to the present invention are useful as gamma secretase modulators. The invention further relates to processes for preparing such novel compounds, pharmaceutical compositions comprising said compounds as an active ingredient as well as the use of said compounds as a medicament.

This invention provides novel compounds that are modulators of gamma secretase. The compounds have the formula (I). Also disclosed are methods of modulating gamma secretase activity and methods of treating Alzheimer's Disease using the compounds of formula (I).

The present invention provides a method of screening for compounds which affect the processing of c-Ret by γ-secretase. The method involves contacting a first biological composition containing γ-secretase or a biologically active fragment thereof with a second biological composition containing c-Ret in the presence and absence of a candidate compound; measuring the cleavage of the c-Ret in the presence and absence of the candidate compound; selecting those candidate compounds which affect the cleavage of the c-Ret by γ-secretase; and identifying the candidate compounds selected in the previous step as compounds which affect the processing of c-Ret by γ-secretase.

The present invention is concerned with novel substituted triazole derivatives of Formula (I)

wherein Het¹, R¹, R², A¹, A², A³, A⁴, L¹, and L² have the meaning defined in the claims. The compounds according to the present invention are useful as gamma secretase modulators. The invention further relates to processes for preparing such novel compounds, pharmaceutical compositions comprising said compounds as an active ingredient as well as the use of said compounds as a medicament.