沈阳药科大学药物化学课件-新药研究与开发概论.ppt

1、OOOOH3COCH3CH3OOOOH3CCH3CH3OHOOOOH3CCH3CH3OCH3OOOOH3CCH3CH3OOONaO H3CNOHCH3H2N NOHCH3NH NOHNHH3C NOHHNNOHNH10 BBBBBBB与A反应 与A反应 ABABABABABABABABCDEFGAAABACADAEAGAF经典合成法组合化学法经典合成法与组合化学法比较 ABCABC模 板线性库分子模板库分子树脂树脂 A A A A A A A A AB B B B B B B B BC C C C C C C C CA A A B B B C C CA A A A A A A A AA A A

2、 B B B C C CB B B B B B B B BA A A B B B C C CC C C C C C C C CA B CA A AA B CB B BA B CC C CA B C A B C A B CA B C A B C A B CA A AB BBBBB B B BC C C C C C C C CA A A A A A均分反应C混匀均分反应A反应B混匀均分A A A B B B C C CA A A B B B C C CA A A B B B C C CA A A B B B C C CA A A B B B C C CA B CA A AA B CB B BA B

3、 CC C CA B C A B C A B CA B C A B C A B C反应C反应A反应BA A A B B B C C CA A A B B B C C C反应C反应A反应B H2NNOCNNNOCNRHN-取代的甘氨酰氰基吡咯烷环己基甘氨酰-2-氰基吡咯烷 1) Fmoc-Proline DIC, DMF2) 20%哌啶/DMF3) BrCH2COOHDIC, DMFBrNOCONHH2N1) 200个胺2) TFANNOCONH2RHTFAANNOCNRHNNOCNRF3CONH3/CH3OH NNOCNNNO2NHHNNOCNNNNCHHIC50 = 8.7 nM（人血浆DP

4、P-IV）IC50 = 7.0 nM（人血浆DPP-IV） BAXYZNONArHHNHNOOORHnXZYNH2RRNNNNH2NRRR OHNNCH3ClOHHHHOHNNRO烷基芳烷基杂芳基OHNNNOHHIC50 = 7.6 M HHRNNNOHHONNNOHHNONNNO KS AT KR ACP KS AT KR ACP TE KS AT ACP KS AT DH ER KR ACPAT ACP KS AT KR ACP KS AT KR ACPSOSOHOSOHOHOSOHOHOOSOHOOHOSOHOHOHOOSOHOHOOHOHO13131313131313139999991555功能单元1功能单元2功能单元3功能单元4功能单元5功能单元6DEBS1DEBS2DEBS3红霉素A6-Deoxyerythronolide BOOCH3HON(CH3)2OHH3COOCH3H3CH3COCH3OOCH3CH3OHOCH3CH3OHHOH3COHH3COOCH3H3CH3COCH3OHOHCH3HOH3C9136129125563