- Control Strategy for the Manufacture of Brivanib Alaninate, a Novel Pyrrolotriazine VEGFR/FGFR Inhibitor
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This manuscript describes the control strategy for the commercial process to manufacture brivanib alaninate. The active pharmaceutical ingredient is a prodrug which is susceptible to hydrolysis. In addition to controlling hydrolysis, a robust strategy was
- Lobben, Paul C.,Barlow, Evan,Bergum, James S.,Braem, Alan,Chang, Shih-Ying,Gibson, Frank,Kopp, Nathaniel,Lai, Chiajen,Laporte, Thomas L.,Leahy, David K.,Müslehiddinolu, Jale,Quiroz, Fernando,Skliar, Dimitri,Spangler, Lori,Srivastava, Sushil,Wasser, Daniel,Wasylyk, John,Wethman, Robert,Xu, Zhongmin
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- Discovery of brivanib alaninate ((S)-((R)-1-(4-(4-fluoro-2-methyl-1H-indol- 5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan-2-yl) 2-aminopropanoate), a novel prodrug of dual vascular endothelial growth factor receptor-2 and fibroblast growth
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A series of amino acid ester prodrugs of the dual VEGFR-2/FGFR-1 kinase inhibitor 1 (BMS-540215) was prepared in an effort to improve the aqueous solubility and oral bioavailability of the parent compound. These prodrugs were evaluated for their ability t
- Cai, Zhen-Wei,Zhang, Yongzheng,Borzilleri, Robert M.,Qian, Ligang,Barbosa, Stephanie,Wei, Donna,Zheng, Xiaoping,Wu, Lawrence,Fan, Junying,Shi, Zhongping,Wautlet, Barri S.,Mortillo, Steve,Jeyaseelan Sr., Robert,Kukral, Daniel W.,Kamath, Amrita,Marathe, Punit,D'Arienzo, Celia,Derbin, George,Barrish, Joel C.,Robl, Jeffrey A.,Hunt, John T.,Lombardo, Louis J.,Fargnoli, Joseph,Bhide, Rajeev S.
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p. 1976 - 1980
(2008/12/22)
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- PROCESS FOR THE PREPARATION OF [(1R), 2S]-2-AMINOPROPIONIC ACID 2-[4-(4-FLUORO-2-METHYL-1H-INDOL-5-YLOXY)-5-METHYLPYRROLO[2,1-f][1,2,4]TRIAZIN-6-YLOXY]-1-METHYLETHYL ESTER
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The invention relates to an improved process for preparing [(1R),2S]-2-aminopropionic acid 2-[4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy]-1-methylethyl ester of the formula: Compound I has been shown to be useful f
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Page/Page column 5; 8-9
(2008/06/13)
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- Discovery and preclinical studies of (R)-1-(4-(4-fluoro-2-methyl-1H-indol- 5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan-2-ol (BMS-540215), an in vivo active potent VEGFR-2 inhibitor
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A series of substituted 4-(4-fluoro-1H-indol-5-yloxy)pyrrolo-[2.1-f][1,2,4] triazine-based inhibitors of vascular endothelial growth factor receptor-2 kinase is reported. Structure-activity relationship studies revealed that a methyl group at the 5-position and a substituted alkoxy group at the 6-position of the pyrrolo[2,1-f][1,2,4]triazine core gave potent compounds. Biochemical potency, kinase selectivity, and pharmacokinetics of the series were optimized and in vitro safety liabilities were minimized to afford BMS-540215 (12), which demonstrated robust preclinical in vivo activity in human tumor xenograft models. The L-alanine prodrug of 12, BMS-582664 (21), is currently under evaluation in clinical trials for the treatment of solid tumors.
- Bhide, Rajeev S.,Cai, Zhen-Wei,Zhang, Yong-Zheng,Qian, Ligang,Wei, Donna,Barbosa, Stephanie,Lombarde, Louis J.,Borzilleri, Robert M.,Zheng, Xiaoping,Wu, Laurence I.,Barrish, Joel C.,Kim, Soong-Hoon,Leavitt, Kenneth,Mathur, Arvind,Leith, Leslie,Chao, Sam,Wautlet, Barri,Mortillo, Steven,Jeyaseelan Sr., Robert,Kukral, Daniel,Hunt, John T.,Kamath, Amrita,Fura, Aberra,Vyas, Viral,Marathe, Punit,D'Arienzo, Celia,Derbin, George,Fargnoli, Joseph
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p. 2143 - 2146
(2007/10/03)
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