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

MEDI 64
Indole-phenylacetic acid inhibitors of CRTH2
Michael G. Johnson, Jiwen Liu, An-Rong Li, Yingcai Wang, Wang Shen, Sarah Lively, Yongli
Su, Bettina van Lengerich, Xuemei Wang, Sujen Lai, Matt Brown, Shauna Lawliss, Ying Sun,
Qingge Xu, Tassie Collins, Jay Danao, Lisa Seitz, Mark Grillo, Jill Wait, and Julio Medina,
Amgen Inc, 1120 Veterans Blvd, San Francisco, CA 94080, mgjohnso@amgen.com
CRTH2 mediates inflammatory cell trafficking and has been identified as a target for the
treatment of asthma. As part of our effort to develop CRTH2 antagonists we discovered a potent
series of indole-phenylacetic acid derivatives that inhibit binding of 3H-PGD2 to CRTH2
receptors on 293 cells and have favorable pharmacokinetic profiles in the rat. However, the
initial representative compounds of this class displayed CYP 3A4 time-dependent inhibition.
Here we describe the optimization of this series of indole derivatives that led to the discovery of
potent CRTH2 antagonists devoid of time-dependent 3A4 inhibition. These compounds and
their analogs may be useful tools for the evaluation of CRTH2 activity in vivo.
MEDI 65
Synthesis and evaluation of a series of 7-substituted-8-azaquinazolinone CXCR3
antagonists
Darin J. Gustin 1 , Phillipe Bergeron 1 , Johann Chan 2 , Xiaoqi Chen 1 , Jeff Diegnan 1 , Du Xiaohui 1 ,
Jeff MIhalic 1 , Theresa Carabeo 1 , Collins Tassie 1 , Lemon Brian 1 , George Tonn 1 , and Julio C.
Medina 1 . (1) Amgen Inc, 1120 Veterans Blvd., South San Francisco, CA 94080,
dgustin@amgen.com, (2) Amgen Inc, Thousand Oaks, CA 91320
CXCR3 is a Gi coupled GPCR receptor that plays an important role in the recruitment of T-cells
to sites of inflammation. Considerable evidence demonstrates that blocking T-cell infiltration has
a benefit in the treatment of immune response mediated diseases. Thus, it is expected that the
development of CXC3 antagonists may find use in the treatment of rheumatoid arthritis (RA)
multiple sclerosis (MS) and cardiac transplant (allograph) rejection. We have previously
described a series of 8-azaquinazolinone based CXCR3 antagonists. As part of our study of
these inhibitors, a series of 7-substituted-8-azaquinazolinones were prepared and evaluated for
CXCR3 binding affinity and for the inhibition of CXCR3 mediated cell migration of human PBMC
cell induced by ITAC. It was found that certain C(7) substituents provided significant potency
improvement in CXCR3 affinity while maintaining good in vivo PK parameters.
MEDI 66
Imidazoacridinones: Potent inhibitors of FLT3 for the treatment of autoimmune diseases
Kenneth W. Duncan, Xinqin Fang, Jennifer L. Christensen, MyDoanh Chau, Keith J. Goodman,
Ann Locniskar, and Alfred M. Ajami, Xanthus Pharmaceuticals Inc, 300 Technology Square,
Cambridge, MA 02139, kenneth.duncan@xanthus.com