Discovery of a Novel Series of Potent, Selective, Orally Available, and Brain-Penetrable C1s Inhibitors for Modulation of the Complement Pathway

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 str...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2023-05, Vol.66 (9), p.6354-6371
Main Authors: Ikeda, Zenichi, Kamei, Taku, Sasaki, Yusuke, Reynolds, Matthew, Sakai, Nozomu, Yoshikawa, Masato, Tawada, Michiko, Morishita, Nao, Dougan, Douglas R., Chen, Chien-Hung, Levin, Irena, Zou, Hua, Kuno, Masako, Arimura, Naoto, Kikukawa, Yusuke, Kondo, Mitsuyo, Tohyama, Kimio, Sato, Kenjiro
Format: Article
Language:English
Subjects:
Brain - metabolism
Complement Activation
Complement C1s - chemistry
Complement C1s - metabolism
Humans
Pharmacology & Pharmacy
Serine Endopeptidases - metabolism
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.3c00348