Replacement of sulfonamide by sulfoximine within a helicase-primase inhibitor with restricted flexibility

Bioorg Med Chem Lett. 2024 Apr 18:129761. doi: 10.1016/j.bmcl.2024.129761. Online ahead of print.ABSTRACTHelicase-primase is an interesting target for the therapy of herpes simplex virus (HSV) infections. Since amenamevir is already approved for varicella-zoster virus (VZV) and HSV in Japan and pritelivir has received breakthrough therapy status for the treatment of acyclovir-resistant HSV infections in immunocompromised patients, the target has sparked interest in me-too approaches. Here, we describe the attempt to improve nervous tissue penetration in Phaeno Therapeutics drug candidate HN0037 to target the latent reservoir of HSV by installing less polar moieties, mainly a difluorophenyl instead of a pyridyl group, and replacing the primary sulfonamide with a methyl sulfoximine moiety. However, all obtained stereoisomers exhibited a weaker inhibitory activity on HSV-1 and HSV-2.PMID:38642810 | DOI:10.1016/j.bmcl.2024.129761
Source: Herpes - Category: Infectious Diseases Authors: Source Type: research