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1.
J Med Chem ; 63(11): 5697-5722, 2020 06 11.
Article in English | MEDLINE | ID: mdl-32073845

ABSTRACT

The alternative pathway (AP) of the complement system is a key contributor to the pathogenesis of several human diseases including age-related macular degeneration, paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), and various glomerular diseases. The serine protease factor B (FB) is a key node in the AP and is integral to the formation of C3 and C5 convertase. Despite the prominent role of FB in the AP, selective orally bioavailable inhibitors, beyond our own efforts, have not been reported previously. Herein we describe in more detail our efforts to identify FB inhibitors by high-throughput screening (HTS) and leveraging insights from several X-ray cocrystal structures during optimization efforts. This work culminated in the discovery of LNP023 (41), which is currently being evaluated clinically in several diverse AP mediated indications.


Subject(s)
Benzoic Acid/chemistry , Complement Factor B/antagonists & inhibitors , Indoles/chemistry , Atypical Hemolytic Uremic Syndrome/metabolism , Atypical Hemolytic Uremic Syndrome/pathology , Benzoic Acid/metabolism , Benzoic Acid/pharmacokinetics , Binding Sites , Catalytic Domain , Complement Factor B/metabolism , Crystallography, X-Ray , Drug Evaluation, Preclinical , Half-Life , Humans , Indoles/metabolism , Indoles/pharmacokinetics , Inhibitory Concentration 50 , Macular Degeneration/metabolism , Macular Degeneration/pathology , Molecular Dynamics Simulation , Structure-Activity Relationship
2.
J Med Chem ; 62(9): 4656-4668, 2019 05 09.
Article in English | MEDLINE | ID: mdl-30995036

ABSTRACT

Complement factor D (FD), a highly specific S1 serine protease, plays a central role in the amplification of the alternative complement pathway (AP) of the innate immune system. Dysregulation of AP activity predisposes individuals to diverse disorders such as age-related macular degeneration, atypical hemolytic uremic syndrome, membranoproliferative glomerulonephritis type II, and paroxysmal nocturnal hemoglobinuria. Previously, we have reported the screening efforts and identification of reversible benzylamine-based FD inhibitors (1 and 2) binding to the open active conformation of FD. In continuation of our drug discovery program, we designed compounds applying structure-based approaches to improve interactions with FD and gain selectivity against S1 serine proteases. We report herein the design, synthesis, and medicinal chemistry optimization of the benzylamine series culminating in the discovery of 12, an orally bioavailable and selective FD inhibitor. 12 demonstrated systemic suppression of AP activation in a lipopolysaccharide-induced AP activation model as well as local ocular suppression in intravitreal injection-induced AP activation model in mice expressing human FD.


Subject(s)
Benzylamines/pharmacology , Complement Pathway, Alternative/drug effects , Serine Proteinase Inhibitors/pharmacology , Animals , Benzylamines/chemical synthesis , Benzylamines/metabolism , Binding Sites , Complement Factor D/antagonists & inhibitors , Complement Factor D/chemistry , Complement Factor D/metabolism , Dogs , Drug Design , Humans , Mice, Inbred C57BL , Mice, Transgenic , Molecular Docking Simulation , Protein Conformation , Rats , Serine Proteinase Inhibitors/chemical synthesis , Serine Proteinase Inhibitors/metabolism
3.
J Biomol Screen ; 19(6): 870-7, 2014 Jul.
Article in English | MEDLINE | ID: mdl-24487225

ABSTRACT

Fluorescence lifetime (FLT)-based assays have developed to become highly attractive tools in drug discovery. All recently published examples of FLT-based assays essentially describe their use for monitoring enzyme-mediated peptide modifications, such as proteolytic cleavage or phosphorylation/dephosphorylation. Here we report the development of competitive binding assays as novel, inhibitor-centric assays, principally employing the FLT of the acridone dye Puretime 14 (PT14) as the readout parameter. Exemplified with two case studies on human serine proteases, the details of the rationale for both the design and synthesis of probes (i.e., active site-directed low-molecular-weight inhibitors conjugated to PT14) are provided. Data obtained from testing inhibitors with the novel assay format match those obtained with alternative formats such as FLT-based protease activity and time-resolved fluorescence resonance energy transfer-based competitive binding assays.


Subject(s)
Drug Discovery/methods , Protease Inhibitors/chemistry , Spectrometry, Fluorescence/methods , Acridones/chemistry , Binding, Competitive , Buffers , Catalytic Domain , Fluorescence Resonance Energy Transfer , Fluorescent Dyes/chemistry , Humans , Hydrogen-Ion Concentration , Inhibitory Concentration 50 , Kinetics , Lung/enzymology , Molecular Conformation , Molecular Weight , Peptides/chemistry , Protein Binding , Recombinant Proteins/chemistry , Serine Proteases/chemistry , Tryptases/chemistry
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