Structure-activity relationship of BMS906024 derivatives for Cryptosporidium parvum growth inhibition

• Authors: Seungheon Lee, University of Houston; Melissa S Love, Scripps Research Institute; Ramkumar Modukuri, Scripps Research Institute; Arnab K Chatterjee, Scripps Research Institute; Lauren Huerta, Scripps Research Institute; Ann P Lawson, Brandeis University; Case W McNamara, Scripps Research Institute; Jan R Mead, Emory University; Lizbeth Hedstrom, Brandeis University; Gregory D Cuny, University of Houston
• Journal Title: BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
• Volume: Volume 90
• Publisher: PERGAMON-ELSEVIER SCIENCE LTD | 2023-05-27, Pages 129328-129328
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1016/j.bmcl.2023.129328
• Subjects: Chemistry, General
• Keywords: Science & Technology; Life Sciences & Biomedicine; Physical Sciences; Chemistry, Medicinal; Chemistry, Organic; Pharmacology & Pharmacy; Chemistry; BUMPED-KINASE INHIBITORS; PAN-NOTCH INHIBITOR; GAMMA-SECRETASE; SELECTIVE INHIBITORS; DISCOVERY; THERAPEUTICS; NITAZOXANIDE; CANDIDATE; EFFICACY; POTENT

Abstract

BMS906024, a γ-secretase inhibitor that blocks Notch signaling, was previously shown to inhibit Cryptosporidium parvum growth in vitro. A structure–activity relationship (SAR) analysis of BMS906024 reported herein demonstrates the importance of the stereochemistry of the C-3 benzodiazepine and the succinyl β-substituent. However, concomitant removal of the succinyl α-substituent and switching the primary amide with secondary amides was tolerated. For example, 32 (SH287) inhibited C. parvum growth in HCT-8 host cells with an EC50 = 6.4 nM and an EC90 = 16 nM; however, blocking C. parvum growth with BMS906024 derivatives was correlative with inhibition of Notch signaling, highlighting that additional SAR analysis will be needed to separate these two activities.