title: 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.
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.
authors.affiliation: 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
authors.forename: Hong-Yu
authors.initials: HY
authors.lastname: Li
authors.forename: William T
authors.initials: WT
authors.lastname: McMillen
authors.forename: Charles R
authors.initials: CR
authors.lastname: Heap
authors.forename: Denis J
authors.initials: DJ
authors.lastname: McCann
authors.forename: Lei
authors.initials: L
authors.lastname: Yan
authors.forename: Robert M
authors.initials: RM
authors.lastname: Campbell
authors.forename: Sreenivasa R
authors.initials: SR
authors.lastname: Mundla
authors.forename: Chi-Hsin R
authors.initials: CH
authors.lastname: King
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Dierks
authors.forename: Bryan D
authors.initials: BD
authors.lastname: Anderson
authors.forename: Karen S
authors.initials: KS
authors.lastname: Britt
authors.forename: Karen L
authors.initials: KL
authors.lastname: Huss
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Voss
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.forename: David K
authors.initials: DK
authors.lastname: Clawson
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Yingling
authors.forename: J Scott
authors.initials: JS
authors.lastname: Sawyer
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology*; D001682:Biological Availability; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D008968:Molecular Conformation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C530108:LY2109761; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011758:Pyrroles; D018125:Receptors, Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625843:Tgfbr1 protein, rat