- 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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- Novel 2,4-disubstituted pyrimidines as potent, selective, and cell-permeable inhibitors of neuronal nitric oxide synthase
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Selective inhibition of neuronal nitric oxide synthase (nNOS) is an important therapeutic approach to target neurodegenerative disorders. However, the majority of the nNOS inhibitors developed are arginine mimetics and, therefore, suffer from poor bioavai
- Mukherjee, Paramita,Li, Huiying,Sevrioukova, Irina,Chreifi, Georges,Martásek, Pavel,Roman, Linda J.,Poulos, Thomas L.,Silverman, Richard B.
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p. 1067 - 1088
(2015/03/04)
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- DIHYDROQUINOLINE-2-ONE DERIVATIVES FOR USE AS ALDOSTERONE SYNTHASE INHIBITORS
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The invention provides novel compounds having the general formula (I) wherein R1, R2, R3, R4, R5, R6, R7, R9, R10 and R11 are as described herein, compositions including the compounds and methods of using the compounds.
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Page/Page column 25
(2014/09/29)
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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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- 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
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- DIHYDROQUINOLINE-2-ONE DERIVATIVES
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The invention provides novel compounds having the general formula (I) wherein R1, R2, R3, R4, R5, R6, R7, A1, A2 and A3 are as described herein, compositions including the compounds and methods of using the compounds. These compounds are useful for therapy or prophylaxis in a mammal, and in particular as aldosterone synthase (CYP11B2 or CYP11B1) inhibitors for the treatment or prophylaxis of chronic kidney disease, congestive heart failure, hypertension, primary aldosteronism and Cushing syndrome.
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Paragraph 0586; 0587
(2013/03/28)
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- NEW DIHYDROQUINOLINE-2-ONE DERIVATIVES
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The invention provides novel compounds having the general formula (I) wherein R1, R2, R3, R4? R5, R6, R7, A1, A2 and A3 are as described herein, compositions including the compounds and methods of using the compounds.
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Page/Page column 84; 85
(2013/03/28)
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- Design and synthesis of active site inhibitors of the human farnesyl pyrophosphate synthase: Apoptosis and inhibition of ERK phosphorylation in multiple myeloma cells
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Human farnesyl pyrophosphate synthase (hFPPS) controls intracellular levels of FPP and post-translational prenylation of small GTPase proteins, which are essential for cell signaling and cell proliferation. Clinical investigations provide evidence that N-BP inhibitors of hFPPS are disease modifying agents that improve survival of multiple myeloma (MM) patients via mechanisms unrelated to their skeletal effects. A new series of N-BPs was designed that interact with a larger portion of the GPP subpocket, as compared to the current therapeutic drugs, and rigidify the 364KRRK367 tail of hFPPS in the closed conformation in the absence of IPP. An analogue of this series was used to demonstrate inhibition of the intended biological target, resulting in apoptosis and down-regulation of ERK phosphorylation in human MM cell lines.
- Lin, Yih-Shyan,Park, Jaeok,De Schutter, Joris W.,Huang, Xian Fang,Berghuis, Albert M.,Sebag, Michael,Tsantrizos, Youla S.
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p. 3201 - 3215
(2012/05/20)
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- QUINAZOLINES AS POTASSIUM ION CHANNEL INHIBITORS
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A compound of formula (I) wherein A, X, Y, Z, R1 and R24 are described herein. The compounds are useful as inhibitors of potassium channel function and in the treatment and prevention of arrhythmia, IKur-associated disorders, and other disorders mediated by ion channel function.
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Page/Page column 287
(2011/04/14)
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- Imidazole derivatives
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Novel imidazole derivatives are disclosed. These compounds have a good affinity to the NMDA (N-methyl-D-aspartate)-receptor subtype selective blockers, which have a key function in modulating neuronal activity and plasticity which makes them key players in mediating processes underlying development of CNS as well as learning and memory formation. These compounds are useful in the control or treatment of diseases mediated by this receptor.
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