- MACROCYCLIC RIP2-KINASE INHIBITORS
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The present invention relates to macrocyclic compounds and compositions containing said compounds acting as kinase inhibitors, in particular as inhibitors of RIP2-kinase, and/or mutants thereof, for use in the diagnosis, prevention and/or treatment of RIP2-kinase associated diseases. Moreover, the present invention provides methods of using said compounds, for instance as a medicine or diagnostic agent.
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Page/Page column 28; 58; 67
(2021/08/06)
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- PYRIDAZINE DERIVATIVES AS SMARCA2/4 DEGRADERS
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The present invention provides pyridazine derivatives of formula (I), which are therapeutically useful as SMARCA2/4 degraders. These compounds are useful in the treatment and/or prevention of diseases or disorders dependent upon SMARCA2/4 in a mammal. The present invention also provides preparation of the compounds and pharmaceutical compositions comprising at least one of the pyridazine derivatives of formula (I) or a pharmaceutically acceptable salt, or a stereoisomer thereof.
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Page/Page column 89-90
(2019/11/12)
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- N-methyl-D-aspartate receptor modulators and methods of making and using same
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Disclosed are compounds having enhanced potency in the modulation of NMDA receptor activity. Such compounds are contemplated for use in the treatment of diseases and disorders, such as learning, cognitive activities, and analgesia, particularly in alleviating and/or reducing neuropathic pain. Orally available formulations and other pharmaceutically acceptable delivery forms of the compounds, including intravenous formulations, are also disclosed.
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- OXADIAZINE COMPOUNDS AND METHODS OF USE THEREOF
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The present disclosure relates to oxadiazine compounds, pharmaceutical compositions comprising an effective amount of an oxadiazine compound and methods for using an oxadiazine compound in the treatment of a neurodegenerative disease, comprising administering to a subject in need thereof an effective amount of an oxadiazine compound.
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Paragraph 0756
(2017/03/14)
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- Discovery of potent and specific dihydroisoxazole inhibitors of human transglutaminase 2
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Transglutaminase 2 (TG2) is a ubiquitously expressed enzyme that catalyzes the posttranslational modification of glutamine residues on protein or peptide substrates. A growing body of literature has implicated aberrantly regulated activity of TG2 in the pathogenesis of various human inflammatory, fibrotic, and other diseases. Taken together with the fact that TG2 knockout mice are developmentally and reproductively normal, there is growing interest in the potential use of TG2 inhibitors in the treatment of these conditions. Targeted-covalent inhibitors based on the weakly electrophilic 3-bromo-4,5-dihydroisoxazole (DHI) scaffold have been widely used to study TG2 biology and are well tolerated in vivo, but these compounds have only modest potency, and their selectivity toward other transglutaminase homologues is largely unknown. In the present work, we first profiled the selectivity of existing inhibitors against the most pertinent TG isoforms (TG1, TG3, and FXIIIa). Significant cross-reactivity of these small molecules with TG1 was observed. Structure-activity and -selectivity analyses led to the identification of modifications that improved potency and isoform selectivity. Preliminary pharmacokinetic analysis of the most promising analogues was also undertaken. Our new data provides a clear basis for the rational selection of dihydroisoxazole inhibitors as tools for in vivo biological investigation.
- Kl?ck, Cornelius,Herrera, Zachary,Albertelli, Megan,Khosla, Chaitan
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p. 9042 - 9064
(2015/03/14)
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- Effect of proline analogues on the conformation of elastin peptides
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Three elastin model peptides containing the repetitive motif -VGVXGVG-, where X corresponds to (2S)-proline (Pro), (2S,4R)-4-hydroxy-proline (Hyp) and (2S,4R)-4-methoxy-proline (Mop), were synthesized in order to define the effect of the introduction of an electronegative group on the conformation and self-assembling properties of the peptides. Circular dichroism, NMR and FT-IR spectroscopies evidenced outstanding differences at molecular and supramolecular level. This work constitutes the basis for the proper design of elastin-inspired drugs with tailored conformational properties.
- Pepe, Antonietta,Crudele, Maria Antonietta,Bochicchio, Brigida
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p. 1326 - 1335
(2013/05/22)
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- Stabilization of the collagen triple helix by O-methylation of hydroxyproline residues
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Collagen is the most abundant protein in animals, including humans. The prevalent (2S,4R)-4-hydroxyproline (Hyp) residues of collagen are known to confer great stability upon its triple-helical conformation. The basis for that stability has been attribute
- Kotch, Frank W.,Guzei, Ilia A.,Raines, Ronald T.
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p. 2952 - 2953
(2008/09/19)
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- PYRROLOTRIAZINE KINASE INHIBITORS
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The invention provides compounds of formula I and pharmaceutically acceptable salts thereof. The formula I compounds inhibit tyrosine kinase activity thereby making them useful as anticancer agents and for the treatment of Alzheimer's Disease.
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Page/Page column 94
(2011/04/19)
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- VLA-4 INHIBITOR
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An object of the present invention is to provide a compound which selectively inhibits binding of a ligand and ±421 integrin (VLA-4), a process for producing the compound, and a medicament containing the compound. A compound represented by the formula (I) etc. orasaltthereof, a process for producing the compound or a salt thereof, a medicament containing the compound or a salt thereof, as well as a preventive and/or a therapeutic agent for a disease caused by cell adhesion, for example, inflammatory reaction, autoimmune disease, cancer metastasis, bronchial asthma, nasal obstruction, diabetes, arthritis, psoriasis, multiple sclerosis, inflammatory bowel disease and rejection reaction at transplantation, containing the compound or a salt thereof as a primary component. [wherein Y 1 represents a divalent aryl group etc. , V 1 represents an aryl group etc., and R 11 to R 14 represent H, OH or a halogen atom etc.]
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- N-Aryl Pyrrolidine Derivatives as Beta-Secretase Inhibitors
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There is provided a series of substituted N-aryl pyrrolidine derivatives of Formula (I) or a stereoisomer; or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R5′, R6, R7, and p as defined herein, their pharmaceutical compositions and methods of use. These compounds inhibit the processing of amyloid precursor protein (APP) by β-secretase and, more specifically, inhibit the production of Aβ-peptide. The present disclosure is directed to compounds useful in the treatment of neurological disorders related to β-amyloid production, such as Alzheimer's disease and other conditions affected by anti-amyloid activity.
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Page/Page column 11
(2010/11/28)
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- Synthesis, biological evaluation, and pharmacokinetic study of prolyl-1-piperazinylacetic acid and prolyl-4-piperidinylacetic acid derivatives as VLA-4 antagonists
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A series of prolyl-1-piperazinylacetic acid and prolyl-4-piperidinylacetic acid derivatives were synthesized and evaluated for their activity as VLA-4 antagonists. Of 22 compounds synthesized, 19 compounds showed potent activity with low nanomolar IC50 values. In addition, the representative compounds 11o and 11p with a hydroxy group in the pyrrolidine ring showed moderate plasma clearance in rats (11o, 30 ml/min/kg and 11p, 21 ml/min/kg) and in dogs (11o, 12 ml/min/kg and 11p, 9 ml/min/kg).
- Chiba, Jun,Takayama, Gensuke,Takashi, Tohru,Yokoyama, Mika,Nakayama, Atsushi,Baldwin, John J.,McDonald, Edward,Moriarty, Kevin J.,Sarko, Christopher R.,Saionz, Kurt W.,Swanson, Robert,Hussain, Zahid,Wong, Angela,MacHinaga, Nobuo
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p. 2725 - 2746
(2007/10/03)
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- STEREOSELECTIVE SYNTHESIS OF N-PROTECTED ALKOXY PROLINES
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A process for preparing optically-active N-protected alkoxy prolines, including (2R,4R)-4-methoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester is disclosed. The N-protected alkoxy prolines are useful for preparing various serine protease factor Xa
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Page/Page column 21
(2010/10/20)
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- VLA-4 INHIBITOR
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A compound which selectively inhibits bonding between a ligand and α4β1 integrin (VLA-4); a process for producing the compound; and a medicine containing the compound. The compound is one represented by, e.g., the formula (I) or a salt thereof. Also provided is a preventive and/or therapeutic agent which contains the compound or salt as a major component and is effective against diseases attributable to cell adhesion, such as, e.g., inflammatory reaction, autoimmune disease, cancer metastasis, bronchial asthma, nasal obstruction, diabetes, arthritis, psoriasis, multiple sclerosis, inflammatory intestinal disease, and rejection reaction in transplantation. (In the formula, Y1 represents arylene, etc.; V1 represents aryl, etc.; and R11 to R14 each represents H, OH, halogeno, etc.)
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Page/Page column 76-77
(2010/02/15)
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- CYANOPYRROLIDINE DERIVATIVES
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A cyanopyrrolidine derivative represented by Formula (1): [wherein R1 is a halogen atom, a hydroxyl group, an alkoxy group having 1 to 5 carbon atoms or an alkyl group having 1 to 5 carbon atoms, R2 is a hydrogen atom, a halogen atom, a hydroxyl group, an alkoxy group having 1 to 5 carbon atoms or an alkyl group having 1 to 5 carbon atoms, or R1 and R2 together form an oxo, a hydroxyimino group, an alkoxyimino group having 1 to 5 carbon atoms or an alkylidene group having 1 to 5 carbon atoms, ???R3 and R4 are each a hydrogen atom, a halogen atom, a hydroxyl group, an alkoxy group having 1 to 5 carbon atoms or an alkyl group having 1 to 5 carbon atoms, or R3 and R4 together form an oxo, a hydroxyimino group, an alkoxyimino group having 1 to 5 carbon atoms or an alkylidene group having 1 to 5 carbon atoms, ???X is an oxygen atom or a sulfur atom, ???Y is -CR5R6- (wherein R5 and R6 are the same or different, and are each a hydrogen atom, a halogen atom, an optionally substituted alkyl group having 1 to 10 carbon atoms or an optionally substituted alkenyl group having 2 to 10 carbon atoms), or -CR7R8-CR9R10- (wherein R7, R8, R9 and R10 are the same or different, and each a hydrogen atom, a halogen atom or an optionally substituted alkyl group having 1 to 10 carbon atoms, or R7 and R9 together with the carbon atom to which they are attached form an optionally substituted cycloalkyl group having 3 to 8 carbon atoms, an optionally substituted cycloalkenyl group having 4 to 8 carbon atoms, an optionally substituted bicycloalkyl group having 5 to 10 carbon atoms, or an optionally substituted bicycloalkenyl group having 5 to 10 carbon atoms) and ???Z is a hydrogen atom or an optionally substituted alkyl group having 1 to 10 carbon atoms, or Y and Z together with the nitrogen atom to which they are attached form an optionally substituted cyclic amino group having 2 to 10 carbon atoms], or a pharmaceutically acceptable salt thereof.
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- Bradykinin type peptides
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The substitution of the L-Pro at the 7-position with D-Phe or D-Tic and substitution of the L-Phe at the 8-position with hydroxyproline ethers and thioethers of the peptide hormone bradykinin and other additional substituted analogs of bradykinin converts bradykinin agonists into bradykinin antagonists. The invention further includes additional modifications at other positions within the novel 7- and 8-position modified bradykinin antagonists, which increase enzyme resistance, antagonist potency, and/or specificity of the new bradykinin antagonists. The analogs produced are useful in treating conditions and diseases of a mammal and human in which an excess of bradykinin or related kinins are produced or injected as by insect bites.
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