Discovery and Development of the Oral Complement Factor D Inhibitor Danicopan (ACH-4471).

Abstract:

:Complement plays a vital role in our innate immune defense against invasive microorganisms. Excessive complement activation or insufficient control of activation on host cells, however, is associated with several chronic disorders. Essential to the activation and amplification of the Alternative Pathway (AP) of complement, Complement Factor D (CFD) is a specific serine protease that cleaves its unique substrate, Complement Factor B (CFB) in complex with an activated form of complement component 3 (C3), to generate the AP C3 convertases C3(H2O)Bb and C3bBb. These convertases comprise a central component in eliciting effector responses following AP activation, and they also enable a powerful amplification loop for both the Classical Pathway (CP) and Lectin Pathway (LP) of complement. Because CFD is not required for the activation of either the CP or LP, selective CFD inhibition presents a favorable therapeutic approach to modulating complement activity that leaves intact the effector functions following CP and LP activation and thus poses a lower risk of bacterial infection than other complement-directed approaches. This review provides an update on inhibitors of CFD, which have evolved from irreversible small molecules that demonstrate poor selectivity to reversible small molecules and monoclonal antibodies that demonstrate exceptional selectivity and potency. The reversible small-molecule inhibitor danicopan.

journal_name

Curr Med Chem

authors

Wiles JA,Galvan MD,Podos SD,Geffner M,Huang M

doi

10.2174/0929867326666191001130342

subject

Has Abstract

pub_date

2020-01-01 00:00:00

pages

4165-4180

issue

25

eissn

0929-8673

issn

1875-533X

pii

CMC-EPUB-101110

journal_volume

27

pub_type

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