Division of Medicinal Chemistry Abstracts-235th ACS National ...

MEDI 82
Synthesis and SAR of 1,2,3,4-tetrahydro-pyrido[2,3-b]pyrazines as c-Met and ALK
inhibitors
Linda R. Weinberg 1 , Mark S. Albom 2 , Thelma S. Angeles 2 , Bruce D. Dorsey 1 , Jean Husten 2 ,
Karen L. Milkiewicz 1 , Seetha Murthy 2 , Douglas A. Pippin 1 , Renee Roemmele 3 , and Ted L.
Underiner 1 . (1) Department of Medicinal Chemistry, Cephalon, Inc, 145 Brandywine Parkway,
West Chester, PA 19380, lweinber@cephalon.com, (2) Department of Lead Discovery and
Profiling, Cephalon, Inc, West Chester, PA 19380, (3) Department of Chemical Process
Research and Development, Cephalon, Inc, Malvern, PA 19355
Dysregulation of c-Met and ALK kinases are implicated in a variety of cancers. c-Met plays a
key role in the proliferation, survival, motility, invasion and metastasis of cancer cells. Activation
of c-Met is implicated in the genesis of papillary renal carcinomas, gastric CA and subsets of
osteo-soft sarcomas. Chromosomal translocations generate multiple ALK oncogenic fusion
proteins in tumors. The NPM-ALK and EML4-ALK proteins play a causative role in the
pathogenesis of anaplastic large-cell lymphoma and non-small cell lung cancer, respectively.
Starting from a Sugen/Pfizer c-Met/ALK dual inhibitor, chemistry was developed to rapidly
elaborate the SAR around a pyridopyrazine scaffold. Analogs from this series were identified
that inhibit c-Met and/or ALK enzyme with IC50 values less than 100 nM. The kinase inhibitory
activity was dependent upon the nature of the X, R and Ar groups.
MEDI 83
Targeted binding of chitosan-based nanoparticles with galactose ligand to HepG2 cells
Ting Wang, Zhangqi Feng, Wenjing Yang, and Nongyue He, State Key Laboratory of
Bioelectronics, Southeast University, Si Pai Lou 2, 210096 Nanjing, China, Fax: 86-25-
83790885, echo2165@163.com, ywjzfh@163.com, nyhe1958@163.com
Solid core-shell polymeric particles are attractive delivery vehicles, because they can efficiently
encapsulate drugs of different physical and chemical characteristics. However, target-tracking
particles for therapeutic purposes have been a somewhat elusive question. In this study we
developed chitosan-based nanoparticles with galactose ligand which has special response
activity with asialoglycoprotein (ASGPR) receptor in the surface carbohydrate of HepG2 cells.
First the chitosan-200 (CS) was modified by lactose acid (LA) to synthesize galactose
conjugated chitosan (Gal-CS) which was detected by FITR and 1H-NMR, the results showed
that the degrees of substitution of LA coupled with chitosan-200 was about 17.6 mol%, then the