1184174-15-9Relevant articles and documents
MK-8353: Discovery of an Orally Bioavailable Dual Mechanism ERK Inhibitor for Oncology
Boga, Sobhana Babu,Deng, Yongqi,Zhu, Liang,Nan, Yang,Cooper, Alan B.,Shipps, Gerald W.,Doll, Ronald,Shih, Neng-Yang,Zhu, Hugh,Sun, Robert,Wang, Tong,Paliwal, Sunil,Tsui, Hon-Chung,Gao, Xiaolei,Yao, Xin,Desai, Jagdish,Wang, James,Alhassan, Abdul Basit,Kelly, Joseph,Patel, Mehul,Muppalla, Kiran,Gudipati, Subrahmanyam,Zhang, Li-Kang,Buevich, Alexei,Hesk, David,Carr, Donna,Dayananth, Priya,Black, Stuart,Mei, Hong,Cox, Kathleen,Sherborne, Bradley,Hruza, Alan W.,Xiao, Li,Jin, Weihong,Long, Brian,Liu, Gongjie,Taylor, Stacey A.,Kirschmeier, Paul,Windsor, William T.,Bishop, Robert,Samatar, Ahmed A.
supporting information, p. 761 - 767 (2018/06/25)
The emergence and evolution of new immunological cancer therapies has sparked a rapidly growing interest in discovering novel pathways to treat cancer. Toward this aim, a novel series of pyrrolidine derivatives (compound 5) were identified as potent inhibitors of ERK1/2 with excellent kinase selectivity and dual mechanism of action but suffered from poor pharmacokinetics (PK). The challenge of PK was overcome by the discovery of a novel 3(S)-thiomethyl pyrrolidine analog 7. Lead optimization through focused structure-activity relationship led to the discovery of a clinical candidate MK-8353 suitable for twice daily oral dosing as a potential new cancer therapeutic.
(S)-N-(3-(6-ISOPROPOXYPYRIDIN-3-YL)-1H-INDAZOL-5-YL)-1-(2-(4-(4-(1-METHYL-1H-1,2,4-TRIAZOL-3-YL)PHENYL)-3,6-DIHYDROPYRIDIN-1(2H)-YL)-2-OXOETHYL)-3-(METHYLTHIO)PYRROLIDINE-3-CARBOXAMIDE COMPOSITIONS FOR PHARMACEUTICAL PREPARATIONS
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Page/Page column 8; 10, (2016/07/05)
The invention includes a granular composition comprising the active ingredient (S)-N-(3-(6-isopropoxypyridin-3-yl)-1H-indazol-5-yl)-1-(2-(4-(4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)-2-oxoethyl)-3-(methylthio)pyrrolidine-3-carboxamide, wherein a total amount of active ingredient comprises by weight % about 60-90% (S)-N-(3-(6-isopropoxypyridin-3-yl)-1H-indazol-5-y1)-1-(2-(4-(4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)-2-oxoethyl)-3-(methylthio)pyrrolidine-3-carboxamide Form 1 HCl, about 10-30% (S)-N-(3-(6-isopropoxypyridin-3-yl)-1H-indazol-5-yl)-1-(2-(4-(4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)-2-oxoethyl)-3-(methylthio)pyrrolidine-3-carboxamide amorphous HCl, and about 0-5% (S)-N-(3-(6-isopropoxypyridin-3-yl)-1H-indazol-5-yl)-1-(2-(4-(4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)-2-oxoethyl)-3-(methylthio)pyrrolidine-3-carboxamide amorphous free base.
(S)-N-(3-(6-ISOPROPOXYPYRIDIN-3-YL)-1H-INDAZOL-5-YL)-1-(2-(4-(4-(1-METHYL-1H-1,2,4-TRIAZOL-3-YL)PHENYL)-3,6-DIHYDROPYRIDIN-1(2H)-YL)-2-OXOETHYL)-3- (METHYLTHIO)PYRROLIDINE-3-CARBOXAMIDE COMPOSITIONS FOR PHARMACEUTICAL PREPARATIONS
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Page/Page column 5; 8, (2016/07/05)
A composition comprising (S)-N-(3-(6-isopropoxypyridin-3-yl)-1H-indazol-5-yl)- 1-(2(4-(4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)-2-oxoethyl)-3- (methylthio)pyrrolidine-3-carboxamide and hypromellose acetate succinate for pharmaceutical preparations, especially capsule preparations.
