- Drug-like property optimization: Discovery of orally bioavailable quinazoline-based multi-targeted kinase inhibitors
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In an effort to develop new cancer therapeutics, we have reported clinical candidate BPR1K871 (1) as a potent anticancer compound in MOLM-13 and MV4-11 leukemia models, as well as in colorectal and pancreatic animal models. As BPR1K871 lacks oral bioavailability, we continued searching for orally bioavailable analogs through drug-like property optimization. We optimized both the physicochemical properties (PCP) as well as in vitro rat liver microsomal stability of 1, with concomitant monitoring of aurora kinase enzyme inhibition as well as cellular anti-proliferative activity in HCT-116 cell line. Structural modification at the 6- and 7-position of quinazoline core of 1 led to the identification of 34 as an orally bioavailable (F% = 54) multi-kinase inhibitor, which exhibits potent anti-proliferative activity against various cancer cell lines. Quinazoline 34 is selected as a promising oral lead candidate for further preclinical evaluation.
- Chang, Chun-Feng,Chen, Chun-Hwa,Chen, Pei-Yi,Coumar, Mohane Selvaraj,Hsieh, Hsing-Pang,Hsu, John T. A.,Kuo, Fu-Ming,Kuo, Po-Chu,Li, An-Siou,Li, Mu-Chun,Lin, Chin-Yu,Lin, Shu-Yu,Lin, Wen-Hsing,Song, Jen-Shin,Wang, Sing-Yi,Yang, Chen-Ming,Yeh, Teng-Kuang
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- CHEMICAL COMPOUNDS
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The invention relates to chemical compounds of the formula (I) or pharmaceutically acceptable salts thereof, which possess B Raf inhibitory activity and are accordingly useful for their anti cancer activity and thus in methods of treatment of the human or animal body. The invention also relates to processes for the manufacture of said chemical compounds, to pharmaceutical compositions containing them and to their use in the manufacture of medicaments of use in the production of an anti-cancer effect in a warm blooded animal such as man.
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Page/Page column 52-53
(2008/06/13)
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- Potential Antimalarials. IX Di-Mannich Bases of 4-(7'-Trifluoromethylquinazolin-4'-ylamino)phenol and 4-(7'-Trifluoromethylquinolin-4'-ylamino)phenol
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Syntheses are reported for a series of di-Mannich bases of 4-(7'-trifluoromethylquinazolin-4'-ylamino)phenol derived from 4-chloro-7-trifluoromethylquinazoline with the di-Mannich bases of 4-aminophenol.Some analogous quinolines were prepared similarly.When tested for antimalarial activity against Plasmodium falciparum in vitro, the quinazolines were rather less active than the corresponding quinolines.
- Barlin, Gordon B.,Jiravinyu, Chuenjit
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p. 311 - 319
(2007/10/02)
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