- FUSED IMIDAZOLE COMPOUNDS
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The present invention provides compounds represented by formula (I), pharmaceutically acceptable salts thereof, N-oxides thereof, solvates thereof or prodrugs thereof (wherein the characters are as defined in the description). The compounds represented by formula (I) have affinity and selectivity for the gamma-aminobutyric acid A receptor subunit alpha 5 (GABAA α5) and act as GABAA α5 negative allosteric modulators (GABAA α5 NAM), so that they are useful in the prevention and/or treatment of diseases which are related to the GABAA α5 such as Alzheimer's disease.
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Page/Page column 80
(2015/09/23)
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- Identification and Optimization of Benzimidazole Sulfonamides as Orally Bioavailable Sphingosine 1-Phosphate Receptor 1 Antagonists with in Vivo Activity
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We report here a novel series of benzimidazole sulfonamides that act as antagonists of the S1P1 receptor, identified by exploiting an understanding of the pharmacophore of a high throughput screening (HTS)-derived series of compounds described previously. Lead compound 2 potently inhibits S1P-induced receptor internalization in a cell-based assay (EC50 = 0.05 μM), but has poor physical properties and metabolic stability. Evolution of this compound through structure-activity relationship development and property optimization led to in vivo probes such as 4. However, this compound was unexpectedly found to be a potent CYP3A inducer in human hepatocytes, and thus further chemistry efforts were directed at addressing this liability. By employing a pregnane X receptor (PXR) reporter gene assay to prioritize compounds for further testing in human hepatocytes, we identified lipophilicity as a key molecular property influencing the likelihood of P450 induction. Ultimately, we have identified compounds such as 46 and 47, which demonstrate the desired S1P1 antagonist activity while having greatly reduced risk of CYP3A induction in humans. These compounds have excellent oral bioavailability in preclinical species and exhibit pharmacodynamic effects of S1P1 antagonism in several in vivo models following oral dosing. Relatively modest antitumor activity was observed in multiple xenograft models, however, suggesting that selective S1P1 antagonists would have limited utility as anticancer therapeutics as single agents.
- Hennessy, Edward J.,Oza, Vibha,Adam, Ammar,Byth, Kate,Castriotta, Lillian,Grewal, Gurmit,Hamilton, Geraldine A.,Kamhi, Victor M.,Lewis, Paula,Li, Danyang,Lyne, Paul,?ster, Linda,Rooney, Michael T.,Saeh, Jamal C.,Sha, Li,Su, Qibin,Wen, Shengua,Xue, Yafeng,Yang, Bin
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p. 7057 - 7075
(2015/09/22)
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- Novel 2,4,5-trisubstituted pyridines as key intermediates for the preparation of the TSPO ligand 6-F-PBR28: Synthesis and full 1H and 13C NMR characterization
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As part of our ongoing research for molecular structures binding to the translocator protein (TSPO 18 kDa), we investigated the preparation of a number of new 2,4,5-trisubstituted pyridines as novel building blocks. In particular, 5-amino-2-halo-4-phenoxypyridines (11, 12, 13) were designed as key intermediates for the synthesis of the recently developed TSPO ligand 6-F-PBR28 and its fluorine-18-labeled version for positron emission tomography, 6-[ 18F]F-PBR28. We hereby report the chemical preparation as well as the 1H and 13C NMR spectroscopic data of polysubstituted pyridines 2, 3, 4, 5, 6, 7, 7b, 8, 9, 10, 11, 12, 13, 14. The latter demonstrates dramatic changes in electron density repartition of the aromatic ring upon substitution.
- Damont, Annelaure,Lemee, Frederic,Raggiri, Guillaume,Dolle, Frederic
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p. 404 - 410
(2014/04/17)
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- Imidazo[4,5-c]pyridine and pyrrolo[3,2-c]pyridine compounds as G-protein-coupled receptor kinase 5 (GRK5) modulators
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The present invention relates to imidazo[5,4-c]pyridine or pyrrolo[3,2-c]pyridine compounds and stereoisomeric forms, solvates, hydrates and/or pharmaceutically acceptable salts of these compounds, as well as pharmaceutical compositions containing at least one of these pyridine-based bicyclic compounds together with pharmaceutically acceptable carrier, excipient and/or diluents. Said pyridine-based bicyclic compounds are assumed to be modulators of the GRK5 protein, thereby regulating the expression and/or release of insulin and are useful for the treatment or prophylaxis of a metabolic disease and in particular for the treatment and prophylaxis of diabetes, obesity and impaired adipogenesis.
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Paragraph 0126; 0128
(2015/01/18)
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- Discovery of aminofurazan-azabenzimidazoles as inhibitors of rho-kinase with high kinase selectivity and antihypertensive activity
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The discovery, proposed binding mode, and optimization of a novel class of Rho-kinase inhibitors are presented. Appropriate substitution on the 6-position of the azabenzimidazole core provided subnanomolar enzyme potency in vitro while dramatically improving selectivity over a panel of other kinases. Pharmacokinetic data was obtained for the most potent and selective examples and one (6n) has been shown to lower blood pressure in a rat model of hypertension. Despite many available treatments, hypertension remains a prevalent problem. In fact, some 30% of hypertensive patients are unable to reach their blood pressure goals. Thus, a new anti-hypertensive treatment, which acts on a broader patient population, would be an important addition to existing treatments. A number of vasoconstrictive agents, including angiotensin II, endothelin-1, and urotensin-II, exert their effect through RhoA and the downstream kinase Rho-kinase (ROCK1).1 Because of its central role in the control of smooth muscle contraction, inhibition of ROCK1 could lead to a more broadly efficacious anti-hypertensive agent.2 ROCK1 inhibitors have been shown to relax vascular smooth muscle and lower blood pressure in several animal models of hypertension.3 Therefore, we began an effort to identify potent ROCK1 inhibitors with pharmacokinetic profiles consistent with once daily oral dosing.
- Stavenger, Robert A.,Cui, Haifeng,Dowdell, Sarah E.,Franz, Robert G.,Gaitanopoulos, Dimitri E.,Goodman, Krista B.,Hilfiker, Mark A.,Ivy, Robert L.,Leber, Jack D.,Marino Jr., Joseph P.,Oh, Hye-Ja,Viet, Andrew Q.,Xu, Weiwei,Ye, Guosen,Zhang, Daohua,Zhao, Yongdong,Jolivette, Larry J.,Head, Martha S.,Semus, Simon F.,Elkins, Patricia A.,Kirkpatrick, Robert B.,Dul, Edward,Khandekar, Sanjay S.,Yi, Tracey,Jung, David K.,Wright, Lois L.,Smith, Gary K.,Behm, David J.,Doe, Christopher P.,Bentley, Ross,Chen, Zunxuan X.,Hu, Erding,Lee, Dennis
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- PYRIDINE DERIVATIVES USEFUL AS INHIBITORS OF PKC-THETA
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Disclosed are novel compounds of formula (I): wherein R1, R2 and R3 are as defined herein, which are useful as inhibitors of PKC-theta and are thus useful for treating a variety of diseases and disorders that are mediated or sustained through the activity of PKC-theta, including immunological disorders and type II diabetes. This invention also relates to pharmaceutical compositions comprising these compounds, methods of using these compounds in the treatment of various diseases and disorders, processes for preparing these compounds and intermediates useful in these processes.
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Page/Page column 13
(2008/06/13)
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- INHIBITORS OF AKT ACTIVITY
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Invented are novel 1 H-imidazo[4,5-c]pyridin-2-yl compounds, the use of such compounds as inhibitors of protein kinase B activity and in the treatment of cancer and arthritis.
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Page/Page column 66
(2008/06/13)
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- CHEMICAL COMPOUNDS
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This invention relates to novel compounds having the formula (I); and to their pharmaceutical compositions and to their methods of use. These novel compounds provide a treatment for cancer.
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Page/Page column 73
(2008/06/13)
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- PREPERATION OF 1,6-DISUBSTITUTED AZABENZIMIDAZOLES AS KINASE INHIBITORS
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Novel inhibitors of Rho-kinases are disclosed.
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Page/Page column 84
(2008/06/13)
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