- Amide compounds and uses thereof
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Provided herein are novel amide compounds of formula (I), pharmaceutical compositions comprising same, methods for preparing same, and uses thereof, wherein the definition of each symbol is as described in the description.
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Page/Page column 145
(2021/10/11)
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- Discovery of a Pyrimidinedione Derivative as a Potent and Orally Bioavailable Axl Inhibitor
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The receptor tyrosine kinase Axl plays important roles in promoting cancer progression, metastasis, and drug resistance and has been identified as a promising target for anticancer therapeutics. We used molecular modeling-assisted structural optimization starting with the low micromolar potency compound 9 to discover compound 13c, a highly potent and orally bioavailable Axl inhibitor. Selectivity profiling showed that 13c could inhibit the well-known oncogenic kinase Met with equal potency to its inhibition of Axl superfamily kinases. Compound 13c significantly inhibited cellular Axl and Met signaling, suppressed Axl- and Met-driven cell proliferation, and restrained Gas6/Axl-mediated cancer cell migration or invasion. Furthermore, 13c exhibited significant antitumor efficacy in Axl-driven and Met-driven tumor xenograft models, causing tumor stasis or regression at well-tolerated doses. All these favorable data make 13c a promising therapeutic candidate for cancer treatment.
- Zhang, Hefeng,Peng, Xia,Dai, Yang,Shao, Jingwei,Ji, Yinchun,Sun, Yiming,Liu, Bo,Cheng, Xu,Ai, Jing,Duan, Wenhu
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supporting information
p. 3956 - 3975
(2021/04/12)
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- Structure-based design of a new series of N-(piperidin-3-yl)pyrimidine-5-carboxamides as renin inhibitors
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The action of the aspartyl protease renin is the rate-limiting initial step of the renin-angiotensin-aldosterone system. Therefore, renin is a particularly promising target for blood pressure as well as onset and progression of cardiovascular and renal diseases. New pyrimidine derivatives 5–14 were designed in an attempt to enhance the renin inhibitory activity of compound 3 identified by our previous fragment-based drug design approach. Introduction of a basic amine essential for interaction with the two aspartic acids in the catalytic site and optimization of the S1/S3 binding elements including an induced-fit structural change of Leu114 (‘Leu-in’ to ‘Leu-out’) by a rational structure-based drug design approach led to the discovery of N-(piperidin-3-yl)pyrimidine-5-carboxamide 14, a 65,000-fold more potent renin inhibitor than compound 3. Surprisingly, this remarkable enhancement in the inhibitory activity of compound 14 has been achieved by the overall addition of only seven heavy atoms to compound 3. Compound 14 demonstrated excellent selectivity over other aspartyl proteases and moderate oral bioavailability in rats.
- Imaeda, Yasuhiro,Tawada, Michiko,Suzuki, Shinkichi,Tomimoto, Masaki,Kondo, Mitsuyo,Tarui, Naoki,Sanada, Tsukasa,Kanagawa, Ray,Snell, Gyorgy,Behnke, Craig A.,Kubo, Keiji,Kuroita, Takanobu
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p. 5771 - 5780
(2016/10/30)
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- PHARMACEUTICAL CONSISTING OF CYCLIC AMINOMETHYL PYRIMIDINE DERIVATIVE
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PROBLEM TO BE SOLVED: To provide a cyclic aminomethyl pyrimidine derivative and a pharmaceutically acceptable salt thereof exhibiting effects on dopamine D4 receptor with high selectivity and useful as a treatment agent of central nervous system diseases such as attention deficit hyperkinesis disorder. SOLUTION: There is provide a compound represented by the formula (1) and a pharmaceutically acceptable salt thereof. (1), where n and m are each independently 1 or 2, Ra is a C1-6 alkyl group, a C3-6 cycloalkyl group or an amino group, Rb is H, a C1-6 alkyl group or an alkyl group-substituted/unsubstituted amino group, Rb is H when Ra is the amino group, Rc1 and Rc2 are each independently H or a C1-6 alkyl group, Rd1 and Rd2 are each independently H, F or a C1-6 alkyl group, a ring Q is substituted/unsubstituted 5- to 10-membered nitrogen-containing heteroaryl group and bond containing break lines is a single bond or a double bond. SELECTED DRAWING: None COPYRIGHT: (C)2016,JPOandINPIT
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Paragraph 0224; 0225
(2016/10/10)
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- CYCLIC AMINOMETHYL PYRIMIDINE DERIVATIVE
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The present invention provides a cyclic aminomethyl pyrimidine derivative and a pharmaceutically acceptable salt thereof with high selectivity for dopamine D4 receptors, which are useful for treating a disease such as attention deficit hyperactivity disorder. Specifically, a compound of formula (1) or a pharmaceutically acceptable salt thereof is provided, wherein n and m are independently 1 or 2; Ra is C1-6 alkyl group, C3-6 cycloalkyl group, or amino group; Rb is hydrogen atom, C1-6 alkyl group or the like, provided that when Ra is amino group, then Rb is hydrogen atom; Rc1 and Rc2 are independently hydrogen atom, or C1-6 alkyl group; Rd1 and Rd2 are independently hydrogen atom, fluorine atom or the like; ring Q is an optionally-substituted pyridyl group or an optionally-substituted isoquinolyl group; and the bond having a dashed line is a single or double bond.
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Paragraph 0293-0295
(2016/06/01)
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- Optimisation of pharmacokinetic properties in a neutral series of 11β-HSD1 inhibitors
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11β-HSD1 is increasingly seen as an attractive target for the treatment of type II diabetes and other elements of the metabolic syndrome. In this program of work we describe how a series of neutral 2-thioalkyl-pyridine 11β-HSD1 inhibitors were optimized in terms of their pharmacokinetic properties to give compounds with excellent bioavailability in both rat and dog through a core change to pyrimidine. A potential reactive metabolite issue with 4-thioalkyl-pyrimidines was circumvented by a switch from sulfur to carbon substitution.
- Scott, James S.,Gill, Adrian L.,Godfrey, Linda,Groombridge, Sam D.,Rees, Amanda,Revill, John,Schofield, Paul,S?rme, Pernilla,Stocker, Andrew,Swales, John G.,Whittamore, Paul R.O.
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p. 6756 - 6761
(2013/01/14)
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- AMIDE COMPOUNDS AND USE OF THE SAME
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A renin inhibitor comprising a compound represented by the formula: wherein each symbol is as defined in the description, or a salt thereof or a prodrug thereof. The compound of the present invention has a superior renin inhibitory activity, and thus is useful as an agent for the prophylaxis or treatment of hypertension, various organ damages attributable to hypertension and the like
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Page/Page column 80
(2012/02/06)
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- SUBSTITUTED PYRIMIDIN-5-CARBOXAMIDES 281
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A compound of formula (I): and pharmaceutically-acceptable salts thereof wherein the variable groups are defined within; their use in the inhibition of 11betaHSD1, processes for making them and pharmaceutical compositions comprising them are also described.
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Page/Page column 117
(2009/10/30)
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- A Novel synthesis of 2-arylpyrrolo[1,2-a]pyrimid-7-ones and their structure-activity relationships as potent GnRH receptor antagonists
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In the process of developing GnRH receptor antagonists, a novel base-catalyzed cyclization of compounds 5a-b was discovered, which led to the formation of the 2-aryl pyrrolo[1,2-a]pyrimid-7-one core stuctures 6a-b. These intermediates were further modifie
- Zhu, Yun-Fei,Wilcoxen, Keith,Saunders, John,Guo, Zhiqiang,Gao, Yinghong,Connors, Jr., Patrick J.,Gross, Timothy D.,Tucci, Fabio C.,Scott Struthers,Reinhart, Greg J.,Xie, Qiu,Chen, Chen
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p. 403 - 406
(2007/10/03)
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- Aromatic heterocyclic derivatives as enzyme inhibitors
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The present invention discloses peptide aldehydes which are potent and specific inhibitors of thrombin, their pharmaceutically acceptable salts, pharmaceutically acceptable compositions thereof, and methods of using them as therapeutic agents for disease states in mammals characterized by abnormal thrombosis.
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Page column 92
(2010/02/04)
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- Novel inhibitors of AP-1 and NF-κB mediated gene expression: Structure-activity relationship studies of ethyl 4-[(3-methyl-2,5-dioxo(3-pyrrolinyl))amino]-2-(trifluoromethyl)pyrimidine-5-carb oxylate
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In an effort to identify novel inhibitors of AP-1 and NF-κB mediated transcriptional activation, several analogues of ethyl 4-[(3-methyl-2,5-dioxo(3-pyrrolinyl))amino]-2-(trifluoromethyl)pyrimidine-5-carb oxylate (1) were synthesized and tested in two in vitro assays. The 2-(2'-thienyl) substituted compound (11) was identified as the most potent in this series. (C) 2000 Elsevier Science Ltd. All rights reserved.
- Palanki, Moorthy S.S.,Erdman, Paul E.,Manning, Anthony M.,Ow, Arnold,Ransone, Lynn J.,Spooner, Cheryl,Suto, Carla,Suto, Mark
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p. 1645 - 1648
(2007/10/03)
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- Aromatic heterocyclic derivatives as enzyme inhibitors
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The present invention discloses peptide aldehydes which are potent and specific inhibitors of thrombin, their pharmaceutically acceptable salts, pharmaceutically acceptable compositions thereof, and methods of using them as therapeutic agents for disease states in mammals characterized by abnormal thrombosis.
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- AROMATIC HETEROCYCLIC DERIVATIVES AS ENZYME INHIBITORS
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The present invention discloses peptide aldehydes which are potent and specific inhibitors of thrombin, their pharmaceutically acceptable salts, pharmaceutically acceptable compositions thereof, and methods of using them as therapeutic agents for disease states in mammals characterized by abnormal thrombosis.
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- Design and synthesis of a novel class of thrombin inhibitors incorporating heterocyclic dipeptide surrogates
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Several potent and selective inhibitors of thrombin incorporating novel heterocyclic peptide surrogates in the P3-P2 position of peptidyl argininals have been discovered. Illustrated in this article are three classes of heterocycles: pyridones, uracils, and pyrimidinones. The synthesis and biological activities of these unique aromatic heterocyclic derivatives are reported herein.
- Tamura, Susan Y.,Semple, J. Edward,Reiner, John E.,Goldman, Erick A.,Brunck, Terence K.,Lim-Wilby, Marguerita S.,Carpenter, Stephen H.,Rote, William E.,Oldeshulte, Gerard L.,Richard, Brigitte M.,Nutt, Ruth F.,Ripka, William C.
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p. 1543 - 1548
(2007/10/03)
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- AROMATIC HETEROCYCLIC DERIVATIVES AS ENZYME INHIBITORS
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The present invention discloses heterocyclic aromatic peptide aldehydes which have an oxopyrimidine or oxopyridine group and an argininal tail which are potent and specific inhibitors of thrombin, their pharmaceutically acceptable salts, pharmaceutically acceptable compositions thereof, and methods of using them as therapeutic agents for disease states in mammals characterized by abnormal thrombosis.
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- AROMATIC HETEROCYCLIC DERIVATIVES AS ENZYME INHIBITORS
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The present invention discloses peptide aldehydes which are potent and specific inhibitors of thrombin, their pharmaceutically acceptable salts, pharmaceutically acceptable compositions thereof, and methods of using them as therapeutic agents for disease states in mammals characterized by abnormal thrombosis.
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- Thiamine Biosynthesis in Yeast - Evaluation of 4-Hydroxy-5-hydroxymethyl-2-methylpyrimidine as a Precursor
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The putative role of 4-hydroxy-5-hydroxymethyl-2-methylpyrimidine 2 as a late precursor in the biosynthesis of thiamine 1 by Saccharomyces cerevisiae has been examined using the deuteriated derivative 2a.To enable measurement of deuterium incorporation into the pyrimidine ring fragment of 1, a procedure for the degradation of 1 to the aniline derivative 6 using thiaminase I from Bacillus thiaminolyticus has been developed.While 4-amino-2-methyl-5-hydroxymethylpyrimidine 3a was incorporated into thiamine, deuterium from hydroxy-pyrimidine 2a was not incorporated to any significant extent, indicating that amination of compound 2 is not a late step in the biosynthesis of the pyrimidine ring.
- Baxter, Robert L.,Hanley, A. Bryan,Chan, Henry W. S.
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p. 2963 - 2966
(2007/10/02)
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