Discovery of the investigational drug TAK-441, a pyrrolo[3,2-c]pyridine derivative, as a highly potent and orally active hedgehog signaling inhibitor: modification of the core skeleton for improved solubility.

Abstract

We recently reported the discovery of the novel pyrrolo[3,2-c]quinoline-4-one derivative 1 as a potent inhibitor of Hedgehog (Hh) pathway signaling. However, the PK evaluation of 1 at high dosage (100 mg/kg) revealed the C(max) value 3.63 μg/mL, likely due to poor solubility of this compound. Efforts to improve solubility by reducing the aromatic ring count of the core system led to N-methylpyrrolo[3,2-c]pyridine derivative 11. Further optimization of the 3-alkoxy group led to compound 11d with acceptable solubility and potent Hh inhibitory activity. Compound 11d suppressed transcription factor Gli1 mRNA expression in tumor-associated stromal tissue and inhibited tumor growth (treatment/control ratio, 3%) in a mouse medulloblastoma allograft model owing to the improved PK profile based on increased solubility. Compound 11d (TAK-441) is currently in clinical trials for the treatment of advanced solid tumors.

• Authors: Tomohiro Ohashi, Yuya Oguro, Toshio Tanaka, Zenyu Shiokawa, Yuta Tanaka, Sachio Shibata, Yoshihiko Sato, Hiroko Yamakawa, Harumi Hattori, Yukiko Yamamoto, Shigeru Kondo, Maki Miyamoto, Mitsuhiro Nishihara, Yoshimasa Ishimura, Hideaki Tojo, Atsuo Baba, Satoshi Sasaki
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 20 Issue 18 Pg. 5507-17 (Sep 15 2012) ISSN: 1464-3391 [Electronic] England
• PMID: 22898254 (Publication Type: Journal Article)
• Copyright: Copyright © 2012 Elsevier Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents
• Gli1 protein, mouse
• Hedgehog Proteins
• Kruppel-Like Transcription Factors
• Pyridines
• Pyrroles
• RNA, Messenger
• TAK-441
• Zinc Finger Protein GLI1
• pyrrolo(3,2-c)pyridine

Topics

• Animals
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Drug Discovery
• Hedgehog Proteins (antagonists & inhibitors, metabolism)
• Humans
• Kruppel-Like Transcription Factors (antagonists & inhibitors, genetics, metabolism)
• Medulloblastoma (drug therapy)
• Mice
• Mice, Nude
• Models, Molecular
• Molecular Structure
• NIH 3T3 Cells
• Pyridines (administration & dosage, chemical synthesis, chemistry, pharmacology)
• Pyrroles (administration & dosage, chemical synthesis, chemistry, pharmacology)
• RNA, Messenger (antagonists & inhibitors, genetics)
• Signal Transduction (drug effects)
• Solubility
• Structure-Activity Relationship
• Transplantation, Homologous
• Zinc Finger Protein GLI1