Protease‐Directed Drug Discovery

Sedrani, Richard; Hommel, Ulrich; Eder, Jörg

doi:10.1002/9780470423936.ch6

Cited by 5 publications

(6 citation statements)

References 78 publications

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“…The core components of the alternative pathway, complement factors D and B, are serine proteases. Serine proteases have been targeted by the pharmaceutic industry for many years and several protease inhibitors have been approved for therapeutic use, for example, direct oral anticoagulants (factor Xa and thrombin inhibitors), anti‐diabetic agents (dipeptidyl peptidase 4 inhibitors) and treatments for hereditary angioedema (plasma kallikrein inhibitors) 7 . In serine proteases, the active site serine mediates the nucleophilic attack at the peptide bond of the substrate protein via a covalent acyl enzyme intermediate and subsequent hydrolysis by water, and substrate specificity is determined by sub‐pockets in the active site.…”

Section: Activation and Regulation Of The Alternative Complement Pathwaymentioning

confidence: 99%

Low‐molecular weight inhibitors of the alternative complement pathway

Schubart

Flohr

Junt

et al. 2022

Immunological Reviews

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The complement system, a major arm of the humoral innate immune system, comprises a cascade of sequentially activated proteases directed at the elimination of pathogens. Deposition of complement components on pathogen surfaces, either directly, or via surfacebound antibodies induces a proteolytic cascade that generates multiple pro-inflammatory protein fragments with diverse functions: Direct cell lysis, chemoattraction and activation of innate immune effector cells, and opsonization, that is, facilitation of pathogen removal by phagocytic cells. As the complement system is a rapid and amplified pro-inflammatory effector system, it needs to be tightly controlled to prevent aberrant and destructive activation. Primary failure of these control mechanisms due to mutations of complement regulators, gain-of function mutations in components of the protease cascade or secondary activation of the complement system due to autoantibodies that stabilize activating complement proteases or neutralize complement regulators or are directed at "self" antigens, all lead to devastating auto-inflammatory diseases.

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Section: Activation and Regulation Of The Alternative Complement Pathwaymentioning

confidence: 99%

Low‐molecular weight inhibitors of the alternative complement pathway

Schubart

Flohr

Junt

et al. 2022

Immunological Reviews

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“…Recognizing the aforementioned challenges, it was clear that the known covalent inhibitors of FB, including pan protease inhibitors nafamostat (FUT-175), sepimostat (FUT-187) as well as various peptide aldehydes, lack the specificity and/or pharmacokinetic profiles suitable for our needs. In addition, it was recognized that some of the unique structural aspects of FB, in particular in the serine protease domain (SPD), may require a different targeting strategy than we have employed with success for other serine proteases. − While FB can exhibit weak catalytic activity against small dipeptides and tripeptides in vitro, in an endogenous setting, full catalytic competency requires an activation event, as is typically the case with chymotrypsin-like serine proteases. In the case of FB this involves binding to C3b, followed by FD mediated release of Ba as described earlier.…”

Section: Results and Discussionmentioning

confidence: 99%

Discovery of 4-((2S,4S)-4-Ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)benzoic Acid (LNP023), a Factor B Inhibitor Specifically Designed To Be Applicable to Treating a Diverse Array of Complement Mediated Diseases

et al. 2020

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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.

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“…We also embarked on a more focused screen of a knowledge-based diversity library (∼1750 compounds) of internal serine protease inhibitors and analogues thereof. This compound collection had been built as part of a protease drug discovery platform at Novartis . While the HTS and FBS efforts delivered several hits that were initially taken forward for structure–activity relationship (SAR) exploration, we eventually became most intrigued by the activity of compound 1 (Figure ), which demonstrated an half maximal inhibitory concentration (IC 50 ) of 0.63 μM against human FXIa and was structurally diverse from known FXIa inhibitors.…”

Section: Results and Discussionmentioning

confidence: 99%

“…Herein we disclose our efforts to identify potent and selective inhibitors of FXIa by leveraging the power of a platform drug discovery approach to target serine proteases . At the outset of this program, we decided to focus exclusively on demonstrating in vitro efficacy and selectivity in combination with high in vivo oral bioavailability for candidate FXIa inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Structure-Based Design and Preclinical Characterization of Selective and Orally Bioavailable Factor XIa Inhibitors: Demonstrating the Power of an Integrated S1 Protease Family Approach

et al. 2020

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The serine protease factor XI (FXI) is a prominent drug target as it holds promise to deliver efficacious anticoagulation without an enhanced risk of major bleeds. Several efforts have been described targeting the active form of the enzyme, FXIa. Herein, we disclose our efforts to identify potent, selective, and orally bioavailable inhibitors of FXIa. Compound 1, identified from a diverse library of internal serine protease inhibitors, was originally designed as a complement factor D inhibitor and exhibited submicromolar FXIa activity and an encouraging absorption, distribution, metabolism, and excretion (ADME) profile while being devoid of a peptidomimetic architecture. Optimization of interactions in the S1, S1β, and S1′ pockets of FXIa through a combination of structure-based drug design and traditional medicinal chemistry led to the discovery of compound 23 with subnanomolar potency on FXIa, enhanced selectivity over other coagulation proteases, and a preclinical pharmacokinetics (PK) profile consistent with bid dosing in patients.

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Protease‐Directed Drug Discovery

Cited by 5 publications

References 78 publications

Low‐molecular weight inhibitors of the alternative complement pathway

Low‐molecular weight inhibitors of the alternative complement pathway

Discovery of 4-((2S,4S)-4-Ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)benzoic Acid (LNP023), a Factor B Inhibitor Specifically Designed To Be Applicable to Treating a Diverse Array of Complement Mediated Diseases

Structure-Based Design and Preclinical Characterization of Selective and Orally Bioavailable Factor XIa Inhibitors: Demonstrating the Power of an Integrated S1 Protease Family Approach

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