- PYRIDINYL AND PYRAZINYL-(AZA)INDOLSULFONAMIDES
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The present invention relates to pyridinyl and pyrazinyl-(aza)indolsulfonamides having GPR17 modulator activity. The compounds have utility in the treatment of a variety of GPR17-associated disorders.
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Page/Page column 59; 81-82
(2020/01/11)
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- Structure-based drug design of novel, potent, and selective azabenzimidazoles (ABI) as ATR inhibitors
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Compound 13 was discovered through morphing of the ATR biochemical HTS hit 1. The ABI series was potent and selective for ATR. Incorporation of a 6-azaindole afforded a marked increase in cellular potency but was associated with poor PK and hERG ion channel inhibition. DMPK experiments established that CYP P450 and AO metabolism in conjunction with Pgp and BCRP efflux were major causative mechanisms for the observed PK. The series also harbored the CYP3A4 TDI liability driven by the presence of both a morpholine and an indole moiety. Incorporation of an adjacent fluorine or nitrogen into the 6-azaindole addressed many of the various medicinal chemistry issues encountered. (Chemical Presented).
- Barsanti, Paul A.,Pan, Yue,Lu, Yipin,Jain, Rama,Cox, Matthew,Aversa, Robert J.,Dillon, Michael P.,Elling, Robert,Hu, Cheng,Jin, Xianming,Knapp, Mark,Lan, Jiong,Ramurthy, Savithri,Rudewicz, Patrick,Setti, Lina,Subramanian, Sharadha,Mathur, Michelle,Taricani, Lorena,Thomas, George,Xiao, Linda,Yue, Qin
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supporting information
p. 42 - 46
(2015/01/30)
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- METHODS OF MAKING NETUPITANT AND INTERMEDIATES THEREOF
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Methods are disclosed for the preparation of netupitant and pharmaceutically acceptable salts thereof which are novel, easily reproducible, environmentally safe and cost effective. The methods may employ inexpensive starting materials and the preparation processes for intermediates are simple and highly reproducible. Novel intermediates for the preparation of netupitant and pharmaceutically acceptable salts thereof are also disclosed. Amorphous netupitant and methods of making same are disclosed.
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Paragraph 0043; 0053
(2015/11/25)
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- Aminofurazans as potent inhibitors of AKT kinase
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AKT inhibitors containing an imidazopyridine aminofurazan scaffold have been optimized. We have previously disclosed identification of the AKT inhibitor GSK690693, which has been evaluated in clinical trials in cancer patients. Herein we describe recent efforts focusing on investigating a distinct region of this scaffold that have afforded compounds (30 and 32) with comparable activity profiles to that of GSK690693.
- Rouse, Meagan B.,Seefeld, Mark A.,Leber, Jack D.,McNulty, Kenneth C.,Sun, Lihui,Miller, William H.,Zhang, ShuYun,Minthorn, Elisabeth A.,Concha, Nestor O.,Choudhry, Anthony E.,Schaber, Michael D.,Heerding, Dirk A.
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scheme or table
p. 1508 - 1511
(2009/11/30)
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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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- 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 36; 62-63
(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 94
(2008/06/13)
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