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). Issue 2 (15th January 2020)

• Record Type: Journal Article
• Authors: Yang, Bin; Hird, Alexander W.; Bodnarchuk, Michael S.; Zheng, Xiaolan; Dakin, Les; Su, Qibin; Daly, Kevin; Godin, Robert; Hattersley, Maureen M.; Brassil, Patrick; Redmond, Sean; John Russell, Daniel; Janetka, James W.
• Is Part Of: Bioorganic & medicinal chemistry. Volume 28:Issue 2(2020)
• Publication Date: 2020-01-15
• Subjects: Hh Hedgehog -- SMO Smoothened -- QM quantum mechanics -- APCI atmospheric pressure chemical ionization -- ATP adenosine 5-triphosphate -- CDCl3 deuterated chloroform -- CI chemical ionization -- EI electron impact -- ESP electrospray -- iv intravenous -- LCMS liquid chromatography-mass spectrometry -- DMSO dimethyl sulfoxide -- PK pharmacokinetics -- PD pharmacodynamics -- EtOAc ethyl acetate -- DCM dichloromethane -- THF tetrahydrofuran -- MgSO4 magnesium sulfate; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2019.115227
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: 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.