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.
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.
Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
Tomohiro
T
Ohashi
Yuya
Y
Oguro
Toshio
T
Tanaka
Zenyu
Z
Shiokawa
Yuta
Y
Tanaka
Sachio
S
Shibata
Yoshihiko
Y
Sato
Hiroko
H
Yamakawa
Harumi
H
Hattori
Yukiko
Y
Yamamoto
Shigeru
S
Kondo
Maki
M
Miyamoto
Mitsuhiro
M
Nishihara
Yoshimasa
Y
Ishimura
Hideaki
H
Tojo
Atsuo
A
Baba
Satoshi
S
Sasaki
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008527:Medulloblastoma / Q000188:drug therapy*; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D015394:Molecular Structure; D041681:NIH 3T3 Cells; D011725:Pyridines / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011758:Pyrroles / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects*; D012995:Solubility; D013329:Structure-Activity Relationship; D014184:Transplantation, Homologous; D000071676:Zinc Finger Protein GLI1
D000970:Antineoplastic Agents; C498520:Gli1 protein, mouse; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D011725:Pyridines; D011758:Pyrroles; D012333:RNA, Messenger; C577980:TAK-441; D000071676:Zinc Finger Protein GLI1; C475261:pyrrolo(3,2-c)pyridine