Discovery of Highly Potent and Selective Small-Molecule Reversible Factor D Inhibitors Demonstrating Alternative Complement Pathway Inhibition in Vivo

Abstract

The highly specific S1 serine protease factor D (FD) plays a central role in the amplification of the complement alternative pathway (AP) of the innate immune system. Genetic associations in humans have implicated AP activation in age-related macular degeneration (AMD), and AP dysfunction predisposes individuals to disorders such as paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS). The combination of structure-based hit identification and subsequent optimization of the center (S)-proline-based lead 7 has led to the discovery of noncovalent reversible and selective human factor D (FD) inhibitors with drug-like properties. The orally bioavailable compound 2 exerted excellent potency in 50% human whole blood in vitro and blocked AP activity ex vivo after oral administration to monkeys as demonstrated by inhibition of membrane attack complex (MAC) formation. Inhibitor 2 demonstrated sustained oral and ocular efficacy in a model of lipopolysaccharide (LPS)-induced systemic AP activation in mice expressing human FD.

Recent Advances in Indazole-Containing Derivatives: Synthesis and Biological Perspectives

“…Lorthiois et al [ 120 ] reported the synthesis of a novel series 1 H -indazole hybrids and investigated their potencies of factor D (FD). During the optimization, compound 198 showed more potent inhibitory activity against FD with an IC 50 value of 0.006 μM in the in vitro membrane attack complex (MAC) deposition assay ( Figure 70 ).…”

<p>Complement system and age-related macular degeneration: drugs and challenges</p>

“…It is usually initiated by C3 convertase to cleave complement C3 into C3a and C3b. Both C3 and C5 convertases play a vital role in forming the final product membrane attack complex (MAC) and cell lysis 20Figure 2Flow diagram shows three separate complement pathways: lectin pathway, alternative pathway and classical pathway (orange box).…”

Incidence of Anaplastic Large Cell Lymphoma and Breast-Implant-Associated Lymphoma—An Analysis of a Certified Tumor Registry over 17 Years

“…Loch-Wilkinson et al identified 38 BI-ALCL cases in total (cases were divided into three different implant types) between 1999 and 2015. Using the reported incidence rates of the implant types gives a total of 1,345,563 implant years and represents an incidence rate of 28.2 (95%-CI: 20-38.8) per 1,000,000 implant years [23].…”

“…Med. 2020, 9, 1247 6 of 10 a total of 1,345,563 implant years and represents an incidence rate of 28.2 (95%-CI: 20-38.8) per 1,000,000 implant years [23].…”