- Discovery of 3-Pyridyl Isoindolin-1-one Derivatives as Potent, Selective, and Orally Active Aldosterone Synthase (CYP11B2) Inhibitors
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Aldosterone synthase (CYP11B2) inhibitors have been explored in recent years as an alternative therapeutic option to mineralocorticoid receptor (MR) antagonists to reduce elevated aldosterone levels, which are associated with deleterious effects on various organ systems including the heart, vasculature, kidney, and central nervous system (CNS). A benzamide pyridine hit derived from a focused screen was successfully developed into a series of potent and selective 3-pyridyl isoindolin-1-ones CYP11B2 inhibitors. Our systematic structure-activity relationship study enabled us to identify unique structural features that result in high selectivity against the closely homologous cortisol synthase (CYP11B1). We evaluated advanced lead molecules, exemplified by compound 52, in an in vivo cynomolgus monkey acute adrenocorticotropic hormone (ACTH) challenge model and demonstrated a superior 100-fold in vivo selectivity against CYP11B1.
- Liu, Yongfu,Wu, Jun,Zhou, Mingwei,Chen, Wenming,Li, Dongbo,Wang, Zhanguo,Hornsperger, Benoit,Aebi, Johannes D.,M?rki, Hans-Peter,Kuhn, Bernd,Wang, Lisha,Kuglstatter, Andreas,Benz, J?rg,Müller, Stephan,Hochstrasser, Remo,Ottaviani, Giorgio,Xin, Jian,Kirchner, Stephan,Mohr, Susanne,Verry, Philippe,Riboulet, William,Shen, Hong C.,Mayweg, Alexander V.,Amrein, Kurt,Tan, Xuefei
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supporting information
p. 6876 - 6897
(2020/08/14)
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- Method for preparing 2-methyl-4-formaldoxime methyl benzoate
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The invention discloses a method for preparing 2-methyl-4-formaldoxime methyl benzoate. The method comprises the following steps: performing acylating chlorination on 2-methyl-4-bromobenzoic acid, carrying out methanol esterification and cyano substitution, and then performing nucleophilic addition elimination with hydroxylamine hydrochloride under alkaline conditions to obtain a target product. The method has the advantages that the process route is simple; reaction conditions are mild; the product yield is high; the total yield reaches 61 percent; the product quality is high; the appearance is white solid; the purity reaches 99.2 percent.
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Paragraph 0015; 0016
(2017/04/03)
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- BICYCLOHETEROARYL-HETEROARYL-BENZOIC ACID COMPOUNDS AS RETINOIC ACID RECEPTOR BETA (RARβ) AGONISTS
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The present invention pertains generally to the field of therapeutic compounds, and more specifically to certain bicycloheteroaryl-heteroaryl-benzoic acid compounds of the following formula (for convenience, collectively referred to herein as "BHBA compou
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Page/Page column 69; 70
(2016/07/05)
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- Development of Bifunctional Inhibitors of Polo-Like Kinase 1 with Low-Nanomolar Activities Against the Polo-Box Domain
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Polo-like kinase 1 (Plk1), a validated cancer target, harbors a protein-protein interaction domain referred to as the polo-box domain (PBD), in addition to its enzymatic domain. Although functional inhibition either of the enzymatic domain or of the PBD has been shown to inhibit Plk1, so far there have been no reports of bifunctional agents with the potential to target both protein domains. Here we report the development of Plk1 inhibitors that incorporate both an ATP-competitive ligand of the enzymatic domain, derived from BI 2536, and a functional inhibitor of the PBD, based either on the small molecule poloxin-2 or on a PBD-binding peptide. Although these bifunctional agents do not seem to bind both protein domains simultaneously, the most potent compound displays low-nanomolar activity against the Plk1 PBD, with excellent selectivity over the PBDs of Plk2 and Plk3. Our data provide insights into challenges and opportunities relating to the optimization of Plk1 PBD ligands as potent Plk1 inhibitors.
- Scharow, Andrej,Knappe, Daniel,Reindl, Wolfgang,Hoffmann, Ralf,Berg, Thorsten
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p. 759 - 767
(2016/04/26)
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- SPIRODIAMINE DERIVATIVES AS ALDOSTERONE SYNTHASE INHIBITORS
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The invention provides compounds having the general formula (I) pharmaceutical compositions containing the compounds and a process for their preparation. The compounds act as aldosterone synthase inhibitors and are for use in the treatment or prevention of chronic kidney disease, congestive heart failure, hypertension, primary aldosteronism and Cushing syndrom.
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Page/Page column 41
(2016/05/02)
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- Novel Imidazoles for the Treatment and Prophylaxis of Respiratory Syncytial Virus Infection
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The invention provides novel compounds having the general formula: wherein R1, R2, R3 and Q are as described herein, compositions including the compounds and methods of using the compounds.
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Paragraph 0223; 0224
(2016/11/28)
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- Modulators of methyl modifying enzymes, compositions and uses thereof
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Agents for modulating methyl modifying enzymes, compositions and uses thereof are provided herein.
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Page/Page column 216; 217
(2015/12/26)
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- IMIDAZOLES FOR THE TREATMENT AND PROPHYLAXIS OF RESPIRATORY SYNCYTIAL VIRUS INFECTION
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The invention provides novel compounds having the general formula: (I) wherein R1, R2, R3 and Q are as described herein, compositions including the compounds and methods of using the compounds.
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Page/Page column 37
(2015/08/06)
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- NEW 3,4-DIHYDRO-2H-ISOQUINOLINE-1-ONE AND 2,3-DIHYDRO-ISOINDOL-1-ONE COMPOUNDS
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The invention provides novel compounds having the general formula (I) wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, A, B, m, n and p are as described herein compositions including the compounds and methods of using the compounds.
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Page/Page column 43
(2014/12/12)
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- NEW 3,4-DIHYDRO-2H-ISOQUINOLINE-1-ONE AND 2,3-DIHYDRO-ISOINDOL-1-ONE COMPOUNDS
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The invention provides novel compounds having the general formula (I) wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, A, m, n and p are as described herein, compositions including the compounds and methods of using the compounds.
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Page/Page column 40
(2014/12/12)
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- NEW 3,4-DIHYDRO-2H-ISOQUINOLINE-1-ONE AND 2,3-DIHYDRO-ISOINDOL-1-ONE COMPOUNDS
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The invention provides novel compounds having the general formula (I) (I) wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, A, m, n and p described herein, compositions including the compounds and methods of using the compounds.
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Page/Page column 41
(2014/12/12)
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- CHROMAN DERIVATIVES AS TRPM8 INHIBITORS
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Chroman compounds and derivatives of Formula I are useful inhibitors of TRPM8. Such compounds are useful in treating a number of TRPM8 mediated disorders and conditions and may be used to prepare medicaments and pharmaceutical compositions useful for treating such disorders and conditions. Examples of such disorders include, but are not limited to, migraines and neuropathic pain. Compounds of Formula I have the following structure: where the definitions of the variables are provided herein.
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Paragraph 0551
(2014/03/21)
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- MODULATORS OF METHYL MODIFYING ENZYMES, COMPOSITIONS AND USES THEREOF
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Agents for modulating methyl modifying enzymes, compositions and uses thereof are provided herein
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Paragraph 00467; 00469
(2013/06/05)
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- NEW BICYCLIC DIHYDROISOQUINOLINE-1-ONE DERIVATIVES
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The invention provides novel compounds having the general formula (I) wherein R1, R2, R3, R4? R5, R6, A1, A2, A3, A4, A5 and n are as described herein,compositions including the compounds and methods of using the compounds as aldosterone synthase (CYP11B2 or CYP11B1) inhibitors for the treatment or prophylaxis of chronic kidney disease, congestive heart failure, hypertension, primary aldosteronism and Cushing syndrom.
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Page/Page column 165
(2013/06/27)
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- AMIDE DERIVATIVE
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Provided are a compound having an excellent hypoglycemic action, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition having an excellent therapeutic effect and/or prophylactic effect on type 1 diabetes, type 2 diabetes, and the like, which cause an increase in the blood sugar level due to abnormal sugar metabolism. A compound represented by general formula (I), or a pharmaceutically acceptable salt thereof, is disclosed.
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Page/Page column 11-12
(2012/06/01)
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- Structure-activity relationships of pyrrole based S-nitrosoglutathione reductase inhibitors: Pyrrole regioisomers and propionic acid replacement
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S-Nitrosoglutathione reductase (GSNOR) is a member of the alcohol dehydrogenase family (ADH) that regulates the levels of S-nitrosothiols (SNOs) through catabolism of S-nitrosoglutathione (GSNO). GSNO and SNOs are implicated in the pathogenesis of many diseases including those in respiratory, cardiovascular, and gastrointestinal systems. The pyrrole based N6022 was recently identified as a potent, selective, reversible, and efficacious GSNOR inhibitor which is currently undergoing clinical development. We describe here the synthesis and structure-activity relationships (SAR) of novel pyrrole based analogues of N6022 focusing on scaffold modification and propionic acid replacement. We identified equally potent and novel GSNOR inhibitors having pyrrole regioisomers as scaffolds using a structure based approach.
- Sun, Xicheng,Qiu, Jian,Strong, Sarah A.,Green, Louis S.,Wasley, Jan W.F.,Colagiovanni, Dorothy B.,Mutka, Sarah C.,Blonder, Joan P.,Stout, Adam M.,Richards, Jane P.,Chun, Lawrence,Rosenthal, Gary J.
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supporting information; experimental part
p. 3671 - 3675
(2011/08/06)
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- NOVEL FIVE-MEMBERED RING COMPOUND
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Disclosed is a five-membered ring compound represented by formula (1) or a pharmaceutically acceptable salt thereof. The compound inhibits infiltration of leukocytes including eosinophils and lymphocytes, and is effective as a drug for treating various inflammations. The compound is highly safe and can be administered for a long period. A pharmaceutical product containing the five-membered ring compound or a pharmaceutically acceptable salt thereof is also disclosed. (In the formula, R1 represents a halogen atom or a phenyl group which may be substituted by a C1-C3 alkyl group or a C1-C3 alkoxy group; R2 represents a C1-C3 alkylene group which may be substituted by a C1-C3 alkyl group or a carbonyl group; R3 represents a C1-C3 alkyl group; R4 and R5 independently represent a hydrogen atom or a C1-C3 alkyl group, or -N(R4)R5 may represent a morpholino group which may be substituted by a C1-C3 alkyl group; Y2 represents a C2-C4 alkylene group; and R6 represents a hydrogen atom, a halogen atom, a C1-C3 alkyl group or a C1-C3 alkoxy group.)
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Page/Page column 14
(2011/02/17)
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- 4 -CYANO- 3 -BENZOYLAMINO-N- PHENYL-BENZAMIDES FOR USE IN PEST CONTROL
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The present invention relates to bis-amide derivatives of formula (I), to processes and intermediates for preparing them,to methods of using them to control insect, acarine, nematode and mollusc pests,and to insecticidal, acaricidal, nematicidal and molluscicidal compositions comprising them.
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Page/Page column 46
(2010/11/18)
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- INSECTICIDAL COMPOUNDS
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The present invention relates to bis-amide derivatives of formula (I), to processes and intermediates for preparing them, to methods of using them to control insect, acarine, nematode and mollusc pests, and to insecticidal, acaricidal, nematicidal and molluscicidal compositions comprising them.
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Page/Page column 32
(2010/11/18)
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- INSECTICIDAL COMPOUNDS
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A compound of formula (I): wherein A1, A2, A3, A4, G1, R1, R2, R3 and R4 are as defined in claim 1; or a salt or N-oxide thereof. Furthermore, the present i
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Page/Page column 35
(2009/07/18)
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- TROPANE COMPOUNDS
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A compound according to Formula I or II: (I) or (II) wherein R1, R1b, R2, L1, and L2 and L2b are as defined in the specification, pharmaceutical compositions thereof, and methods of use thereof.
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Page/Page column 430
(2009/05/30)
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- METHODS OF MODULATING NEUROTROPHIN-MEDIATED ACTIVITY
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Disclosed are compositions which modulate the interaction with nerve growth factor and precursors thereof with neurotrophic receptors. Also disclosed are methods of using the compositions of the invention, including methods of administration.
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Page/Page column 41-42
(2009/04/24)
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- Novel cyclic amide derivatives
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Novel compounds represented by the following formula (I) that act as a ligand to sigma receptor/binding cite and a medicament comprising the same as an active ingredient: wherein X represents an alkyl group, an aryl group, a heterocyclic group or the like; Q represents a group represented by —CH2—, —CO—, —O—, —CH(OR7)— or the like wherein R7 represents a hydrogen atom, an alkyl group or the like; n represents an integer of from 0 to 5; R1 and R2 each represent a hydrogen atom, an alkyl group or the like; B represents either of the following groups: wherein R3, R4, R5, and R6 each represent a hydrogen atom, a halogen atom, an alkoxyl group or the like; m represents 1 or 2; and the ring of: represents an aromatic heterocyclic ring.
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- QUINOLINE DERIVATIVE
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This invention relates to a compound (a quinoline derivative) represented by the formula (I): STR1 The quinoline derivative of this invention has a strong leukotriene antagonistic action and is extremely useful as an antiallergic medicine and an anti-inflammatory medicine.
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