Low-molecular weight inhibitors of the alternative complement pathway

Abstract

Dysregulation of the alternative complement pathway predisposes individuals to a number of diseases. It can either be evoked by genetic alterations in or by stabilizing antibodies to important pathway components and typically leads to severe diseases such as paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, C3 glomerulopathy, and age-related macular degeneration. In addition, the alternative pathway may also be involved in many other diseases where its amplifying function for all complement pathways might play a role. To identify specific alternative pathway inhibitors that qualify as therapeutics for these diseases, drug discovery efforts have focused on the two central proteases of the pathway, factor B and factor D. Although drug discovery has been challenging for a number of reasons, potent and selective low-molecular weight (LMW) oral inhibitors have now been discovered for both proteases and several molecules are in clinical development for multiple complement-mediated diseases. While the clinical development of these inhibitors initially focuses on diseases with systemic and/or peripheral tissue complement activation, the availability of LMW inhibitors may also open up the prospect of inhibiting complement in the central nervous system where its activation may also play an important role in several neurodegenerative diseases.

Keywords: alternative complement pathway; complement factor B; complement factor D; complement therapeutics; drug discovery; low-molecular weight inhibitor.

FIGURE 1

Protease function in the alternative pathway. (A) Proteolytic activation of the alternative complement pathway. For detailed description see text. (B) Schematic representation of the active site of proteases, indicating individual binding pockets of the protease (S, blue) and corresponding substrate amino acids (P, red), N‐terminally (non‐prime, dark colors) or C‐terminally (prime, light colors) of the scissile bond

FIGURE 2

Potential indications for antagonists of the alternative complement pathway. Clinical development of factor D and factor B antagonists has been pursued in diseases of low heterogeneity and a high level of preclinical and pharmacological validation. Area of circles represents prevalence of the diseases (PNH 0.1/100.000, C3G: 0.2/100.000, aHUS: 0.3/100′000, dry AMD: 440/100′000, CAD 1.6/100′000, ITP: 9.5/100′000, IgAN: 2.5/100′000; ANCA vasculitis: 5–18/100′000; SLE: 20–150/100′000) and hatched circles indicate that clinical responses to alternative pathway antagonists may vary between patient subgroups

FIGURE 3

Low molecular weight inhibitors of factor D. (A) Prototypic covalent factor D inhibitors. (1) 3,4‐Dichloroisocoumarin, (2) 6‐Amidino‐2‐naphthyl 4‐guanidino benzoate (FUT‐175). (3) BCX‐1470 (Biocryst). (B) Proline‐based factor D inhibitors. (4) from Novartis; (5) danicopan and (6) vemircopan from Achillion/Alexion. (C) Crystal structure of the complex between human factor D (green) and compound (4) (magenta, PDB code 5NB7) expanding from the S1 pocket into the S1 and S2 prime site. (D) Representative examples from benzylamine and benzylamide‐based factor D inhibitors extracted from publications and patents. Compounds (7), (8), (9) from Novartis and (10) from Biocryst. (E) Crystal structure of the complex between human factor D (green) and compound (8) (magenta, PDB code 6QMR) with extended H‐bond network of aminopropanol motif of ligand to Asp189, Ser190, Ile227 and Thr214 in S1 pocket

FIGURE 4

Low molecular weight inhibitors of factor B. (A) Iptacopan (12) was developed from a fragment‐like high‐throughput screening hit (11), by optimizing interactions in the S1 and in the extended S3 pocket., (B) Crystal structure of the complex between human factor B (green) and iptacopan (magenta, PDB code 6RAV). The indole moiety is binding into the S1 pocket and the piperidine core into the S3 pocket; Shown are key hydrogen bonds to Thr190 and Gly216, respectively. (C) Representative examples of factor B inhibitors with different structural motifs compared to iptacopan extracted from Novartis patents: (13), (14) and (15)