Design, synthesis, and evaluation of oxyanion-hole selective inhibitor substituents for the S1 subsite of factor Xa

Rumthao, Sochanchingwung; Lee, Oukseub; Sheng, Quan Z.; Fu, Wentao; Mulhearn, Debbie C.; Crich, David; Mesecar, Andrew D.; Johnson, Michael E.

doi:10.1016/j.bmcl.2004.07.054

Cited by 8 publications

(2 citation statements)

References 38 publications

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“…Direct elaboration of the naphthyl ring did not appear promising when considering what appeared to be a relatively tight fit of the 2-bromine and 4-methyl substituents. The naphthyl core also did not offer tractable trajectories to grow the molecule into the oxyanion hole, a common means of enhancing potency. , In addition, the apolar nature of the naphthyl would potentially make it more challenging to create positive interactions with the relatively polar S1 pocket. However, the X-ray structure suggested that replacing the naphthyl core with an indole would be advantageous.…”

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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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 oxyanion hole, indispensable for proteolytic activity, plays a role in the substrate binding and stabilization of the tetrahedral transition intermediate containing the oxyanion through polar interactions with the main-chain amides of the conserved GDSG motif (39,40). Interestingly, the crystal structure of AVCP⌬2 shows altered conformation of its oxyanion hole (Fig.…”

Section: Fig 4 Structural Comparison Of the Hydrophobic Pockets Betwementioning

confidence: 99%

trans -Protease Activity and Structural Insights into the Active Form of the Alphavirus Capsid Protease

Aggarwal

Dhindwal

Kumar

et al. 2014

J Virol

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The alphavirus capsid protein (CP) is a serine protease that possesses cis-proteolytic activity essential for its release from the nascent structural polyprotein. The released CP further participates in viral genome encapsidation and nucleocapsid core formation, followed by its attachment to glycoproteins and virus budding. Thus, protease activity of the alphavirus capsid is a potential antialphaviral target to arrest capsid release, maturation, and structural polyprotein processing. However, the discovery of capsid protease inhibitors has been hampered due to the lack of a suitable screening assay and of the crystal structure in its active form. Here, we report the development of a trans-proteolytic activity assay for Aura virus capsid protease (AVCP) based on fluorescence resonance energy transfer (FRET) for screening protease inhibitors. Kinetic parameters using fluorogenic peptide substrates were estimated, and the K m value was found to be 2.63 ؎ 0.62 M while the k cat /K m value was 4.97 ؋ 10 4 M ؊1 min ؊1 . Also, the crystal structure of the trans-active form of AVCP has been determined to 1.81-Å resolution. Structural comparisons of the active form with the crystal structures of available substrate-bound mutant and inactive blocked forms of the capsid protease identify conformational changes in the active site, the oxyanion hole, and the substrate specificity pocket residues, which could be critical for rational drug design. IMPORTANCEThe alphavirus capsid protease is an attractive antiviral therapeutic target. In this study, we have described the formerly unap- , the disordered C-terminal residues after His261, and the presence of a water molecule in the oxyanion hole of AVCP⌬2 (AVCP with a deletion of the last two residues at the C terminus) reveal the effect of the C-terminal Trp267 deletion on enzyme structure. New structural data reported in this study along with the fluorogenic assay will be useful in substrate specificity characterization, high-throughput protease inhibitor screening, and structure-based development of antiviral drugs.

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Design, Syntheis, and Evaluation of Oxyanion‐Hole Selective Inhibitor Substituents for the S1 Subsite of Factor Xa.

Rumthao¹,

Lee²,

Sheng³

et al. 2005

ChemInform

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Organo-phosphorus compounds S 0080 Design, Syntheis, and Evaluation of Oxyanion-Hole Selective Inhibitor Substituents for the S1 Subsite of Factor Xa. -[design, synthesis and evaluation of a series of p-amidinophenylsulfones (III), -amines (VI) and phosphinic acids (X) for their factor Xa inhibitory activity]. -(RUMTHAO, S.; LEE, O.; SHENG, Q.; FU, W.; MULHEARN, D. C.; CRICH, D.; MESECAR, A. D.; JOHNSON*, M. E.; Bioorg.

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Design, synthesis, and evaluation of oxyanion-hole selective inhibitor substituents for the S1 subsite of factor Xa

Cited by 8 publications

References 38 publications

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

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

trans -Protease Activity and Structural Insights into the Active Form of the Alphavirus Capsid Protease

Design, Syntheis, and Evaluation of Oxyanion‐Hole Selective Inhibitor Substituents for the S1 Subsite of Factor Xa.

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