- Allyl amine compound and application thereof
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The invention belongs to the technical field of medicines, and particularly relates to an allyl amine compound shown as a formula I or pharmaceutically acceptable salt, ester, stereoisomer and tautomer thereof, wherein R1, R2, R3, R4, R5, R6, L1 and Cy1 are defined in the specification. The invention also relates to pharmaceutical preparations and pharmaceutical compositions containing the compound, and application of the compound in prevention and/or treatment of diseases related to SSAO/VAP-1 protein or mediated by the SSAO/VAP-1 protein.
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- 4-aminopyrrolopyrimidine derivative and preparation method and application thereof
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The invention relates to a 4-aminopyrrolopyrimidine derivative and a preparation method and application thereof, and belongs to the field of medicines. The invention provides a compound shown as a formula I or pharmaceutically acceptable salt thereof. The
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Paragraph 0137-0138; 0141; 0151-0152
(2020/05/14)
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- Synthesis and Pharmacological Evaluation of Noncatechol G Protein Biased and Unbiased Dopamine D1 Receptor Agonists
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Noncatechol heterocycles have recently been discovered as potent and selective G protein biased dopamine 1 receptor (D1R) agonists with superior pharmacokinetic properties. To determine the structure-activity relationships centered on G protein or β-arrestin signaling bias, systematic medicinal chemistry was employed around three aromatic pharmacophores of the lead compound 5 (PF2334), generating a series of new molecules that were evaluated at both D1R Gs-dependent cAMP signaling and β-arrestin recruitment in HEK293 cells. Here, we report the chemical synthesis, pharmacological evaluation, and molecular docking studies leading to the identification of two novel noncatechol D1R agonists that are a subnanomolar potent unbiased ligand 19 (PW0441) and a nanomolar potent complete G protein biased ligand 24 (PW0464), respectively. These novel D1R agonists provide important tools to study D1R activation and signaling bias in both health and disease.
- Wang, Pingyuan,Felsing, Daniel E.,Chen, Haiying,Raval, Sweta R.,Allen, John A.,Zhou, Jia
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supporting information
p. 792 - 799
(2019/05/02)
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- CANCER TREATMENTS TARGETING CANCER STEM CELLS
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Disclosed are compounds, methods, compositions, and kits that allow for treating cancer by, e.g., targeting cancer stem cells. In some embodiments, the cancer is colorectal cancer, gastric cancer, gastrointestinal stromal tumor, ovarian cancer, lung cancer, breast cancer, pancreatic cancer, prostate cancer, testicular cancer, or lymphoma. In some embodiments, the cancer is liver cancer, endometrial cancer, leukemia, or multiple myeloma. The compounds utilized in the disclosure are of Formula (0), (O'), and (I):
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Paragraph 0331; 0337-0339
(2019/11/19)
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- Identification of 5-(2,3-Dihydro-1 H-indol-5-yl)-7 H-pyrrolo[2,3- d]pyrimidin-4-amine Derivatives as a New Class of Receptor-Interacting Protein Kinase 1 (RIPK1) Inhibitors, Which Showed Potent Activity in a Tumor Metastasis Model
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We herein report the structural optimization and structure-activity relationship studies of 5-(2,3-dihydro-1H-indol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine derivatives as a new class of receptor-interacting protein kinase 1 (RIPK1) inhibitors. Among all obtained RIPK1 inhibitors, 1-(5-{4-amino-7-ethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2,3-dihydro-1H-indol-1-yl)-2-[3-(trifluoromethoxy)phenyl]ethan-1-one (22b) is the most active one. This compound potently inhibited RIPK1 with a binding affinity (KD) of 0.004 μM and an enzymatic IC50 value of 0.011 μM and also showed good kinase selectivity. It could efficiently protect cells from necroptosis and attenuate the necrotic cell death of vascular endothelial cells induced by tumor cells both in vitro and in vivo. Importantly, compound 22b exhibited excellent antimetastasis activity in the experimental B16 melanoma lung metastasis model. It also displayed favorable pharmacokinetic properties. Collectively, 22b could be a promising agent for preventing tumor metastasis.
- Li, Yueshan,Xiong, Yu,Zhang, Guo,Zhang, Liting,Yang, Wei,Yang, Jiao,Huang, Luyi,Qiao, Zeen,Miao, Zhuang,Lin, Guifeng,Sun, Qiu,Niu, Ting,Chen, Lijuan,Niu, Dawen,Li, Linli,Yang, Shengyong
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p. 11398 - 11414
(2019/01/08)
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- 4,5,6,7-TETRAHYDRO-1 H-PYRAZOLO[4,3-C]PYRIDIN-3-AMINE COMPOUNDS AS CBP AND/OR EP300 INHIBITORS
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The present invention relates to compounds of formula (I) or formula (II): and to salts thereof, wherein R1-R4 of formula (I) and R1-R3 of formula (II) have any of the values defined herein, and compositions and uses thereof. The compounds are useful as inhibitors of CBP and/or EP300. Also included are pharmaceutical compositions comprising a compound of formula (I) of formula (II) or a pharmaceutically acceptable salt thereof, and methods of using such compounds and salts in the treatment of various CBP and/or EP300-mediated disorders.
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Page/Page column 300
(2016/06/14)
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- HETEROCYCLIC CGRP RECEPTOR ANTAGONISTS
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The present invention is directed to heterocyclic compounds which are antagonists of CGRP receptors and may be useful in the treatment or prevention of diseases in which CGRP is involved, such as migraine. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which CGRP is involved.
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Page/Page column 81
(2016/05/19)
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- Pesticidal compositions and processes related thereto
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This document discloses molecules having the following formula (“Formula One”): and processes associated therewith.
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- Discovery of a novel series of N-phenylindoline-5-sulfonamide derivatives as potent, selective, and orally bioavailable Acyl CoA:monoacylglycerol acyltransferase-2 inhibitors
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Acyl CoA:monoacylglycerol acyltransferase-2 (MGAT2) has attracted interest as a novel target for the treatment of obesity and metabolic diseases. Starting from N-phenylbenzenesulfonamide derivative 1 with moderate potency for MGAT2 inhibition, we explored
- Sato, Kenjiro,Takahagi, Hiroki,Yoshikawa, Takeshi,Morimoto, Shinji,Takai, Takafumi,Hidaka, Kousuke,Kamaura, Masahiro,Kubo, Osamu,Adachi, Ryutaro,Ishii, Tsuyoshi,Maki, Toshiyuki,Mochida, Taisuke,Takekawa, Shiro,Nakakariya, Masanori,Amano, Nobuyuki,Kitazaki, Tomoyuki
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supporting information
p. 3892 - 3909
(2015/05/27)
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- INDOLINE DERIVATIVES AS INHIBITORS OF PERK
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The invention is directed to substituted indoline derivatives. Specifically, the invention is directed to compounds according to Formula I: (I) wherein R1, R2 and R3 are defined herein. The compounds of the invention are inhibitors of PERK and can be usef
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Page/Page column 73; 74
(2015/05/05)
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- PESTICIDAL COMPOSITIONS AND PROCESSES RELATED THERETO
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This document discloses molecules having the following formula (“Formula One”): and processes associated therewith.
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- PESTICIDAL COMPOSITIONS AND PROCESSES RELATED THERETO
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This document discloses molecules having the following formula ("Formula One"): and processes associated therewith.
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- PESTICIDAL COMPOSITIONS AND PROCESSES RELATED THERETO
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This document discloses molecules having the following formula (“Formula One”): and processes associated therewith.
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- PESTICIDAL COMPOSITIONS AND PROCESSES RELATED THERETO
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This document discloses molecules having the following formula ("Formula One") and processes associated therewith.
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- PESTICIDAL COMPOSITIONS AND PROCESSES RELATED THERETO
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This document discloses molecules having the following formula (“Formula One”): and processes associated therewith.
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- Novel pyridyl- or isoquinolinyl-substituted indolines and indoles as potent and selective aldosterone synthase inhibitors
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Pathologically, high levels of aldosterone are associated with severe cardiovascular diseases such as congestive heart failure, hypertension, and myocardial fibrosis. The inhibition of aldosterone synthase (CYP11B2) to reduce aldosterone levels has been proposed as a promising treatment for diseases related to CYP11B2 because it is the crucial enzyme in the biosynthesis of aldosterone. A series of novel pyridyl- or isoquinolinyl-substituted indolines and indoles was designed via a ligand-based approach. The synthesized compounds were tested and found to be strong CYP11B2 inhibitors. The most potent ones showed IC50 values of less than 3 nM, being similarly potent as fadrozole and LCI699. Among them, compounds 14 and 23 showed good selectivity over the highly homologous CYP11B1, with selectivity factors (SF = IC 50 CYP11B1/IC50 CYP11B2) around 170; thus, they are superior to fadrozole and LCI699 (SFs 50 > 50 μM) of a panel of hepatic CYP enzymes including CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 and the crucial steroidogenic enzymes, CYP17 and CYP19. Because of these advantageous profiles, compounds 14 and 23 are considered to be candidates for further in vivo evaluation.
- Yin, Lina,Hu, Qingzhong,Emmerich, Juliette,Lo, Michael Man-Chu,Metzger, Edward,Ali, Amjad,Hartmann, Rolf W.
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supporting information
p. 5179 - 5189
(2014/07/08)
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- PESTICIDAL COMPOSITIONS AND PROCESSES RELATED THERETO
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This document discloses molecules having the following formula (“Formula One”): and processes associated therewith.
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- ANTIMICROBIAL 4-OXOQUINOLIZINES
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This invention provides novel 4-oxoquinolizine compounds and their uses for a series of broad-spectrum antibiotics having no cross-resistance to existing or emerging classes of antibiotics. In addition the novel 4-oxoquinolizine compounds are useful again
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Page/Page column 200; 201
(2012/08/27)
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- BICYCLIC HETEROARYL COMPOUNDS AS GPR119 RECEPTOR AGONISTS
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The present invention provides a new class of bicyclic heteroaryl compounds represented by Formula (I), pharmaceutical compositions containing these compounds, and their use for modulating the activity of GPR119 in the treatment of metabolic disorders and complications thereof, as well as methods for the treatment of the metabolic disorders and complications thereof.
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Page/Page column 47
(2012/08/27)
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- Discovery of 7-methyl-5-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro- 1H-indol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (GSK2606414), a potent and selective first-in-class inhibitor of protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK)
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Protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) is activated in response to a variety of endoplasmic reticulum stresses implicated in numerous disease states. Evidence that PERK is implicated in tumori-genesis and cancer cell survival stim
- Axten, Jeffrey M.,Medina, Jesús R.,Feng, Yanhong,Shu, Arthur,Romeril, Stuart P.,Grant, Seth W.,Li, William Hoi Hong,Heerding, Dirk A.,Minthorn, Elisabeth,Mencken, Thomas,Atkins, Charity,Liu, Qi,Rabindran, Sridhar,Kumar, Rakesh,Hong, Xuan,Goetz, Aaron,Stanley, Thomas,Taylor, J. David,Sigethy, Scott D.,Tomberlin, Ginger H.,Hassell, Annie M.,Kahler, Kirsten M.,Shewchuk, Lisa M.,Gampe, Robert T.
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p. 7193 - 7207
(2012/11/07)
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- CHEMICAL COMPOUNDS
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The invention is directed to substituted indoline derivatives. Specifically, the invention is directed to compounds according to Formula I wherein R1, R2 and R3 are defined herein. The compounds of the invention are inhibitors of PERK and can be useful in the treatment of cancer, ocular diseases, and diseases associated with activated unfolded protein response pathways, such as Alzheimer?s disease, stroke, Type 1 diabetes Parkinson disease, Huntington?s disease, amyotrophic lateral sclerosis, myocardial infarction, cardiovascular disease, atherosclerosis, and arrhythmias, and more specifically cancers of the breast, colon, pancreatic, and lung. Accordingly, the invention is further directed to pharmaceutical compositions comprising a compound of the invention. The invention is still further directed to methods of inhibiting PERK activity and treatment of disorders associated therewith using a compound of the invention or a pharmaceutical composition comprising a compound of the invention.
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Page/Page column 86
(2011/10/13)
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- Arylpiperazine derivatives and uses thereof
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Compounds of the formula: or pharmaceutically acceptable salts thereof, wherein m, n, X, Y, Z, Ar, R1, R2, R3, R4, R5, R6 and R7 are defined herein. Also provided are pharmaceuti
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Page/Page column 28
(2008/06/13)
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- Synthesis and evaluation of indolinyl- and indolylphenylacetylenes as PET imaging agents for β-amyloid plaques
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Two new phenylacetylene derivatives, 5-((4-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)phenyl)ethynyl)indoline 8 and 5-((4-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)phenyl)ethynyl)-1H-indole 14, targeting β-amyloid (Aβ) plaques have been prepared. In vitro binding carr
- Qu, Wenchao,Choi, Seok-Rye,Hou, Catherine,Zhuang, Zhiping,Oya, Shunichi,Zhang, Wei,Kung, Mei-Ping,Manchandra, Rajesh,Skovronsky, Daniel M.,Kung, Hank F.
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body text
p. 4823 - 4827
(2009/05/30)
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- Sulfonamide bicyclic compounds
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The invention encompasses compounds of Formula I, including pharmaceutically acceptable salts and solvates, their pharmaceutical compositions, and their uses in inhibiting β-amyloid peptide (β-AP) production.
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Page/Page column 11
(2010/10/20)
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- Thienopyridine and furopyridine kinase inhibitors
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Compounds having the formula are useful for inhibiting protein tyrosine kinases. The present invention also discloses methods of making the compounds, compositions containing the compounds, and methods of treatment using the compounds.
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- Pyrazolo-[4,3-e]-1,2,4-triazolo-[1,5-c]-pyrimidine adenosine A2a receptor antagonists
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Compounds having the structural formula I or a pharmaceutically acceptable salt thereof, wherein R is optionally substituted phenyl, furanyl, thienyl, pyridyl, pyridyl N-oxide, oxazolyl or pyrrolyl, or cycloalkenyl R1, R2, R3, R4 and R5 are H, alkyl or alkoxyalkyl; and Z is optionally substituted aryl or heteroaryl are disclosed. Also disclosed is the use of compounds of formula I in the treatment of central nervous system diseases, in particular Parkinson's disease, alone or in combination with other agents for treating Parkinson's disease, and pharmaceutical compositions comprising them.
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Page/Page column 19
(2008/06/13)
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- Beta-aminoacid-derivatives as factor Xa inhibitors
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The present invention relates to compounds of the formula I, in which R0 ; R1 ; R2 ; R3 ; R4; R5, R6, Q; V, G and M have the meanings indicated in the claims. The compounds of the formula I are valuable pharmacologically active compounds. They exhibit a strong antithrombotic effect and are suitable, for example, for the therapy and prophylaxis of cardiovascular disorders like thromboembolic diseases or restenoses. They are reversible inhibitors of the blood clotting enzymes factor Xa (FXa) and/or factor VIIa (FVIIa), and can in general be applied in conditions in which an undesired activity of factor Xa and/or factor VIIa is present or for the cure or prevention of which an inhibition of factor Xa and/or factor VIIa is intended. The invention furthermore relates to processes for the preparation of compounds of the formula I, their use, in particular as active ingredients in pharmaceuticals, and pharmaceutical preparations comprising them.
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- QUINOLINE-DERIVED AMIDE MODULATORS OF VANILLOID VR1 RECEPTOR
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This invention is directed to vanilloid receptor VR1 ligands. More particularly, this invention relates to quinoline-derived amides that are potent antagonists or agonists of VR1 which are useful for the treatment and prevention of inflammatory and other pain conditions in mammals.
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- 2-Alkynyl-and 2-alkenyl-pyrazolo-[4,3-e]-1,2,4-triazolo-[1,5-c]-pyrimidine adenosine A2a receptor antagonists
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Compounds having the structural formula I or a pharmaceutically acceptable salt thereof, wherein R is R1, R2, R3, R4 and R5 are H, alkyl or alkoxyalkyl; R6 is H, alkyl, hydroxyalkyl or —CH2F; R7, R8 and R9 are H, alkyl, alkoxy, alkylthio, alkoxyalkyl, halo or —CF3; and Z is optionally substituted aryl, heteroaryl or heteroaryl-alkyl are disclosed. Also disclosed is the use of compounds of formula I in the treatment of central nervous system diseases, in particular Parkinson's disease, alone or in combination with other agents for treating Parkinson's disease, and pharmaceutical compositions comprising them.
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- AMIDE DERIVATIVES AND THEIR USE AS INHIBITORS OF 11-BETA-HYDROXYSTEROID DEHYDROGENASE TYPE 1
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Compounds of the formula (I) provide pharmacological agents which lower intracellular glucocorticoid concentrations in mammals, in particular, intracellular cortisol levels in humans. Therefore, the compounds of the instant invention improve insulin sensitivity in the muscle and the adipose tissue, and reduce lipolysis and free fatty acid production in the adipose tissue. The compounds of the invention lower hepatic glucocorticoid concentration in mammals, in particular, hepatic cortisol concentration in humans, resulting in inhibition of hepatic gluconeogenesis and lowering of plasma glucose levels. Thus, the compounds of the instant invention may be particularly useful in mammals as hypoglycemic agents for the treatment and prevention of conditions in which hyperglycemia and/or insulin resistance are implicated, such as type-2 diabetes. The compounds of the invention may also be used to treat other glucocorticoid associated disorders, such as Syndrome-X, dyslipidemia, hypertension and central obesity. The invention furthermore relates to the use of the compounds according to the invention for the preparation of medicaments, in particular of medicaments useful for the treatment and prevention of glucocorticoid associated disorders, by improving insulin sensitivity, reducing plasma glucose levels, reducing lipolysis and free fatty acid production, and by decreasing visceral adipose tissue formation.
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- Aza-bicycles which modulate the inhibition of cell adhesion
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The invention is directed to physiologically active compounds of formula (I) wherein R1represents R3—Z3—, R3—L2—R4—Z3—, R3—L3—Ar1—L4—Z3— or R3—L3—Ar1—L2—R4—Z3—; R2represents hydrogen, halogen, lower alkyl or lower alkoxy; A1represents a straight chain C1-3alkylene linkage optionally substituted by one or more groups chosen from alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, imino, oxo, thioxo, or alkyl substituted by —ZR6, —NY1Y2, —CO2R6or —C(═O)—NY1Y2; L1represents a direct bond; an alkenylene, alkylene, alkynylene, cycloalkenylene, cycloalkylene, heteroaryldiyl, heterocycloalkylene or arylene linkage each optionally substituted by (a) an acidic functional group, cyano, oxo, —S(O)mR9, R3, —C(═O)—R3, —C(═O)—OR3, —N(R8)—C(═O)R9, —N(R8)—SO2—R9, —NY4Y5or —[C(═O)—N(R10)—C(R5)(R11)]p—C(═O)—NY4Y5, or by (b) alkyl substituted by an acidic functional group, or S(O)mR9, —C(═O)—NY4Y5or —NY4Y5; a —[C(═O)—N(R10)—C(R5)(R11)]p— linkage; a —Z2—R12— linkage; a —C(═O)—CH2—C(═O)— linkage; a —R12—Z2—R12— linkage; a —C(R4)(R13)—[C(═O)—N(R10)—C(R5)(R11)]p— linkage; or a —L5—L6—L7— linkage; Z1is C(R7)(R7a), C(═O) or CH(OH); Y is carboxy or an acid bioisostere; and the corresponding N-oxides, and their prodrugs; and pharmaceutically acceptable salts and solvates of such compounds and their N-oxides and prodrugs. Such compounds have valuable pharmaceutical properties, in particular the ability to regulate the interaction of VCAM-1 and fibronectin with the integrin VLA-4 (α4β1).
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- Inhibitors of factor Xa
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Novel compounds, their salts and compositions related thereto having activity against mammalian factor Xa are disclosed. The compounds of formula (I) below: are useful in vitro or in vivo for preventing or treating coagulation disorders.
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