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Publication Abstract from PubMed

A novel series of non-amidine-based C1s inhibitors have been explored. Starting from high-throughput screening hit 3, isoquinoline was replaced with 1-aminophthalazine to enhance C1s inhibitory activity while exhibiting good selectivity against other serine proteases. We first disclose a crystal structure of a complex of C1s and a small-molecule inhibitor (4e), which guided structure-based optimization around the S2 and S3 sites to further enhance C1s inhibitory activity by over 300-fold. Improvement of membrane permeability by incorporation of fluorine at the 8-position of 1-aminophthalazine led to identification of (R)-8 as a potent, selective, orally available, and brain-penetrable C1s inhibitor. (R)-8 significantly inhibited membrane attack complex formation induced by human serum in a dose-dependent manner in an in vitro assay system, proving that selective C1s inhibition blocked the classical complement pathway effectively. As a result, (R)-8 emerged as a valuable tool compound for both in vitro and in vivo assessment.

Discovery of a Novel Series of Potent, Selective, Orally Available, and Brain-Penetrable C1s Inhibitors for Modulation of the Complement Pathway.,Ikeda Z, Kamei T, Sasaki Y, Reynolds M, Sakai N, Yoshikawa M, Tawada M, Morishita N, Dougan DR, Chen CH, Levin I, Zou H, Kuno M, Arimura N, Kikukawa Y, Kondo M, Tohyama K, Sato K J Med Chem. 2023 May 11;66(9):6354-6371. doi: 10.1021/acs.jmedchem.3c00348. Epub , 2023 Apr 25. PMID:37120845^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.