title: Synthesis and evaluation of hedgehog signaling inhibitor with novel core system.
abstract: As we previously reported, N-methylpyrrolo[3,2-c]pyridine derivatives 1 (TAK-441) was discovered as a clinical candidate of hedgehog (Hh) signaling inhibitor by modification of the upper part. We next focused on modification of the lower part including core skeletons to discover new Hh signaling inhibitors with novel core rings. Efforts to find novel chemotypes by using X-ray single crystal structure analysis led to some potent Hh signaling inhibitors (2c, 2d, 2e, 2f) with novel core ring systems, which had benzamide moiety at the 5-position as a key component for potent activity. The suppression of Gli1 expression with these new Hh signaling inhibitors were weaker than that of compound 1 (TAK-441) because of low pharmacokinetic property. We recognized again TAK-441 is a good compound as clinical candidate with good structural and pharmacokinetic advantages.
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Limited, 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: tomohiro.oohashi@takeda.com.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Ohashi
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Limited, 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Tanaka
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Limited, 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Zenyu
authors.initials: Z
authors.lastname: Shiokawa
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Limited, 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Banno
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Limited, 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Tanaka
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Limited, 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Sachio
authors.initials: S
authors.lastname: Shibata
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Limited, 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Satoh
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Limited, 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Yamakawa
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Limited, 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Yamamoto
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Limited, 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Harumi
authors.initials: H
authors.lastname: Hattori
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Limited, 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Kondo
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Limited, 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Maki
authors.initials: M
authors.lastname: Miyamoto
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Limited, 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Tojo
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Limited, 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Atsuo
authors.initials: A
authors.lastname: Baba
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Limited, 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: satoshi.sasaki@takeda.com.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Sasaki
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical; D017930:Genes, Reporter; D006207:Half-Life; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008968:Molecular Conformation; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D053823:Hedgehog Proteins; D011725:Pyridines; D011758:Pyrroles; C577980:TAK-441; C023666:pyridine
keywords: Benzamide; Dihedral angle; Hedgehog; Hh signaling inhibitor; TAK-441; X-ray single crystal structure