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

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

doi:10.1016/j.bmc.2012.07.034

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

Bioorg Med Chem. 2012 Sep 15;20(18):5507-17. doi: 10.1016/j.bmc.2012.07.034. Epub 2012 Jul 27.

Authors

Tomohiro Ohashi¹, 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

Affiliation

¹ Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.

PMID: 22898254
DOI: 10.1016/j.bmc.2012.07.034

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.

MeSH terms

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

Substances

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