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PMID: 18314943 Published · ppublish English Journal Article

Optimization of a dihydropyrrolopyrazole series of transforming growth factor-beta type I receptor kinase domain inhibitors: discovery of an orally bioavailable transforming growth factor-beta receptor type I inhibitor as antitumor agent.

Journal of medicinal chemistry ·Vol. 51 ·No. 7 ·2008-04-10 ·Pages 2302-6

Li HY, McMillen WT, Heap CR, McCann DJ, Yan L, Campbell RM, Mundla SR, King CH, Dierks EA, Anderson BD, Britt KS, Huss KL, Voss MD, Wang Y, Clawson DK, Yingling JM, Sawyer JS

Abstract

In our continuing effort to expand the SAR of the quinoline domain of dihydropyrrolopyrazole series, we have discovered compound 15d, which demonstrated the antitumor efficacy with oral bioavailability. This effort also demonstrated that the PK/PD in vivo target inhibition paradigm is an effective approach to assess potential for antitumor efficacy. The dihydropyrrolopyrazole inhibitor 15d (LY2109761) is representative of a novel series of antitumor agents.

MeSH Terms
Administration, Oral Animals Antineoplastic Agents/administration & dosage,chemistry,pharmacology Biological Availability Cell Proliferation/drug effects Crystallography, X-Ray Drug Design Humans Mice Mice, Nude Models, Molecular Molecular Conformation Protein Kinase Inhibitors/administration & dosage,chemistry,pharmacology Protein Serine-Threonine Kinases/antagonists & inhibitors Pyrazoles/chemical synthesis,chemistry,pharmacology Pyrroles/chemical synthesis,chemistry,pharmacology Rats Receptor, Transforming Growth Factor-beta Type I Receptors, Transforming Growth Factor beta/antagonists & inhibitors Stereoisomerism Structure-Activity Relationship Xenograft Model Antitumor Assays
Chemicals
Antineoplastic Agents LY2109761 Protein Kinase Inhibitors Pyrazoles Pyrroles Receptors, Transforming Growth Factor beta Protein Serine-Threonine Kinases Receptor, Transforming Growth Factor-beta Type I Tgfbr1 protein, rat
Authors & Affiliations
17 authors, click to expand affiliations / ORCID
Li Hong-Yu
Discovery Chemistry Research and Technology, Lead Optimization Biology, and Chemical Product Research and Development, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. li_hong-yu@lilly.com
McMillen William T
Heap Charles R
McCann Denis J
Yan Lei
Campbell Robert M
Mundla Sreenivasa R
King Chi-Hsin R
Dierks Elizabeth A
Anderson Bryan D
Britt Karen S
Huss Karen L
Voss Matthew D
Wang Yan
Clawson David K
Yingling Jonathan M
Sawyer J Scott
Article Info
Journal
Journal of medicinal chemistry
Abbr.
J Med Chem
ISSN
0022-2623
DOI
10.1021/jm701199p
Email
li_hong-yu@lilly.com
Published
2008-04-10
Epub
2008-00-04
Pages
2302-6
Language
English
Region
United States
NLM ID
9716531
Subset
IM
External Links
PubMed source DOI: 10.1021/jm701199p View journal details
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