Heteroarylamide smoothened inhibitors: Discovery of N-[2,4-dimethyl-5-(1-methylimidazol-4-yl)phenyl]-4-(2-pyridylmethoxy)benzamide (AZD8542) and N-[5-(1H-imidazol-2-yl)-2,4-dimethyl-phenyl]-4-(2- pyridylmethoxy)benzamide (AZD7254).

Autor: Yang B; Medicinal Chemistry, Oncology, IMED Biotech Unit, AstraZeneca, 35 Gatehouse Drive, Waltham, MA 02451, USA. Electronic address: byang@kymeratx.com., Hird AW; Medicinal Chemistry, Oncology, IMED Biotech Unit, AstraZeneca, 35 Gatehouse Drive, Waltham, MA 02451, USA., Bodnarchuk MS; Medicinal Chemistry, Oncology, IMED Biotech Unit, AstraZeneca, Building 310, Cambridge Science Park, Milton Road, Cambridge, UK., Zheng X; Medicinal Chemistry, Oncology, IMED Biotech Unit, AstraZeneca, 35 Gatehouse Drive, Waltham, MA 02451, USA., Dakin L; Medicinal Chemistry, Oncology, IMED Biotech Unit, AstraZeneca, 35 Gatehouse Drive, Waltham, MA 02451, USA., Su Q; Medicinal Chemistry, Oncology, IMED Biotech Unit, AstraZeneca, 35 Gatehouse Drive, Waltham, MA 02451, USA., Daly K; Medicinal Chemistry, Oncology, IMED Biotech Unit, AstraZeneca, 35 Gatehouse Drive, Waltham, MA 02451, USA., Godin R; Bioscience, Oncology, IMED Biotech Unit, AstraZeneca, 35 Gatehouse Drive, Waltham, MA 02451, USA., Hattersley MM; Bioscience, Oncology, IMED Biotech Unit, AstraZeneca, 35 Gatehouse Drive, Waltham, MA 02451, USA., Brassil P; Drug Metabolism and Pharmacokinetics, Oncology, IMED Biotech Unit, AstraZeneca, 35 Gatehouse Drive, Waltham, MA 02451, USA., Redmond S; Oncology Safety, Drug Safety and Metabolism, IMED Biotech Unit, AstraZeneca, 35 Gatehouse Drive, Waltham, MA 02451, USA., John Russell D; Medicinal Chemistry, Oncology, IMED Biotech Unit, AstraZeneca, 35 Gatehouse Drive, Waltham, MA 02451, USA., Janetka JW; Medicinal Chemistry, Oncology, IMED Biotech Unit, AstraZeneca, 35 Gatehouse Drive, Waltham, MA 02451, USA.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry [Bioorg Med Chem] 2020 Jan 15; Vol. 28 (2), pp. 115227. Date of Electronic Publication: 2019 Dec 11.
DOI: 10.1016/j.bmc.2019.115227
Abstrakt: Aberrant hedgehog (Hh) pathway signaling is implicated in multiple cancer types and targeting the Smoothened (SMO) receptor, a key protein of the Hh pathway, has proven effective in treating metastasized basal cell carcinoma. Our lead optimization effort focused on a series of heteroarylamides. We observed that a methyl substitution ortho to the heteroaryl groups on an aniline core significantly improved the potency of this series of compounds. These findings predated the availability of SMO crystal structure in 2013. Here we retrospectively applied quantum mechanics calculations to demonstrate the o-Me substitution favors the bioactive conformation by inducing a dihedral twist between the heteroaryl rings and the core aniline. The o-Me also makes favorable hydrophobic interactions with key residue side chains in the binding pocket. From this effort, two compounds (AZD8542 and AZD7254) showed excellent pharmacokinetics across multiple preclinical species and demonstrated in vivo activity in abrogating the Hh paracrine pathway as well as anti- tumor effects.
(Copyright © 2019 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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