- Potent, Orally Bioavailable, and Efficacious Macrocyclic Inhibitors of Factor XIa. Discovery of Pyridine-Based Macrocycles Possessing Phenylazole Carboxamide P1 Groups
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Factor XIa (FXIa) inhibitors are promising novel anticoagulants, which show excellent efficacy in preclinical thrombosis models with minimal effects on hemostasis. The discovery of potent and selective FXIa inhibitors which are also orally bioavailable has been a challenge. Here, we describe optimization of the imidazole-based macrocyclic series and our initial progress toward meeting this challenge. A two-pronged strategy, which focused on replacement of the imidazole scaffold and the design of new P1 groups, led to the discovery of potent, orally bioavailable pyridine-based macrocyclic FXIa inhibitors. Moreover, pyridine-based macrocycle 19, possessing the phenylimidazole carboxamide P1, exhibited excellent selectivity against relevant blood coagulation enzymes and displayed antithrombotic efficacy in a rabbit thrombosis model.
- Corte, James R.,Pinto, Donald J. P.,Fang, Tianan,Osuna, Honey,Yang, Wu,Wang, Yufeng,Lai, Amy,Clark, Charles G.,Sun, Jung-Hui,Rampulla, Richard,Mathur, Arvind,Kaspady, Mahammed,Neithnadka, Premsai Rai,Li, Yi-Xin Cindy,Rossi, Karen A.,Myers, Joseph E.,Sheriff, Steven,Lou, Zhen,Harper, Timothy W.,Huang, Christine,Zheng, Joanna J.,Bozarth, Jeffrey M.,Wu, Yiming,Wong, Pancras C.,Crain, Earl J.,Seiffert, Dietmar A.,Luettgen, Joseph M.,Lam, Patrick Y. S.,Wexler, Ruth R.,Ewing, William R.
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supporting information
p. 784 - 803
(2020/02/04)
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- NOVEL OXADIAZOLE DERIVATIVE AND PHARMACEUTICAL CONTAINING SAME
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An amyloid fibril formation inhibitor comprising a compound represented by the following general formulae (I) to (III): wherein Q is -C(=O)-; X is -C(=O)-, -NH-C(=O)-; Y is -(CH2)m-; Z is -(CH2)n-; R1
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Paragraph 0118; 0119
(2018/02/28)
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- The discovery of new plant activators and scaffolds with potential induced systemic resistance: From jasmonic acid to pyrrolidone
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Plants can develop multifaceted system resistance as a result of infection with pathogens, insects, and some specific microbes or after treatment with specific chemicals.1 Among them, systemic acquired resistance (SAR) and induced systemic resi
- Chang, Kang,Shi, Yanxia,Chen, Jianqin,He, Zenghui,Xu, Zheng,Zhao, Zhenjiang,Zhu, Weiping,Li, Honglin,Xu, Yufang,Li, Baoju,Qian, Xuhong
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p. 1849 - 1857
(2016/09/23)
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- TETRAHYDROISOQUINOLINES CONTAINING SUBSTITUTED AZOLES AS FACTOR XIA INHIBITORS
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The present invention provides compounds of Formula (I), or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein all the variables are as defined herein. These compounds are selective factor XIa inhibitors or dual inhibitors of FXIa and plasma kallikrein. This invention also relates to pharmaceutical compositions comprising these compounds and methods of treating thromboembolic and/or inflammatory disorders using the same.
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Page/Page column 123
(2014/10/15)
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- NOVEL MACROCYCLES AS FACTOR XIA INHIBITORS
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The present invention provides compounds of Formula (Ia): or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein all the variables are as defined herein. These compounds are selective factor XIa inhibitors or dual inhibitors of FXIa and plasma kallikrein. This invention also relates to pharmaceutical compositions comprising these compounds and methods of treating thromboembolic and/or inflammatory disorders using the same.
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Paragraph 00337
(2013/03/26)
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- N-Aryl pyrrolidinonyl oxadiazoles as potent mGluR5 positive allosteric modulators
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A novel series of N-aryl pyrrolidinonyl oxadiazoles were identified as mGluR5 positive allosteric modulators (PAMs). Optimization of the initial lead compound 6a led to the identification of the 12c (-) enantiomer as a potent compound with acceptable in vitro clearance, CYP, hERG and PK properties. Para substituted N-aryl pyrrolidinonyl oxadiazoles are mGluR5 PAMs while the meta and ortho substituted N-aryl pyrrolidinonyl oxadiazoles are negative allosteric modulators (NAMs). Para fluoro substitution on the N-aryl group and meta chloro or methyl substituents on the aryl oxadiazole moiety are optimal for mGluR5 PAM efficacy. The existence of an exquisitely sensitive 'PAM to NAM switch' within this chemotype making it challenging for simultaneous optimization of potency and drug-like properties.
- Packiarajan, Mathivanan,Mazza Ferreira, Christine G.,Hong, Sang-Phyo,White, Andrew D.,Chandrasena, Gamini,Pu, Xiaosui,Brodbeck, Robbin M.,Robichaud, Albert J.
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scheme or table
p. 5658 - 5662
(2012/09/22)
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- Synthesis of 4-methyloxybenzoic acids and related compounds, and their inhibitory capacities toward fatty-acid and sterol biosynthesis
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The synthesis of a series of 4-methyloxybenzoic acids and related compounds, and their evaluation for inhibitory capacity toward fatty-acid and sterol biosyntheses using rats' liver slices in vitro and rabbits
- Watanabe, S.,Ogawa, K.,Ohno, T.,Yano, S.,Yamada, H.,Shirasaka, T.
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p. 675 - 686
(2007/10/02)
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