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

ID: ALA5247664

Journal: Bioorg Med Chem Lett

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

Authors: Lee S, Love MS, Modukuri R, Chatterjee AK, Huerta L, Lawson AP, McNamara CW, Mead JR, Hedstrom L, Cuny GD.

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.

CiteXplore: 37196868

DOI: 10.1016/j.bmcl.2023.129328

Patent ID: ┄