Design and synthesis of polyethylene glycol-modified biphenylsulfonyl-thiophene-carboxamidine inhibitors of the complement component C1s

Subasinghe, Nalin L.; Khalil, Ehab M.; Travins, Jeremy; Ali, Farah; Ballentine, Shelley K.; Hufnagel, Heather; Pan, Wenxi; Leonard, Kristi; Bone, Roger; Söll, Richard; Crysler, Carl; Ninan, Nisha; Kirkpatrick, Jennifer; Kolpak, Michael X.; DiLoreto, Karen; Eisennagel, Stephen; Huebert, Norman; Molloy, Christopher J.; Tomczuk, Bruce E.; Gaul, Michael D.

doi:10.1016/j.bmcl.2012.06.030

Cited by 7 publications

(23 citation statements)

References 15 publications

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“…Traditionally, selective blockage of the CP has focused on its major activating serine protease C1s, yet attempts to arrive at small molecule inhibitors were hampered by poor specificity and pharmacokinetics (11). More recently, structure-guided discovery approaches and PEG-ylation were able to improve such shortcomings and may lead to clinical C1s inhibitors (12, 13). In addition to small molecule approaches, antibody-centered strategies to prevent pattern recognition by C1q have also shown promise; for example, the single chain antibody fragment scFv(QuVHVL) that binds to the globular heads of C1q was shown to block recognition of both IgG and C-reactive protein and to largely reduce CP activation by apoptotic cells (14).…”

Section: The Therapeutic Arsenal To Tackle Complement-related Diseasesmentioning

confidence: 99%

Complement in Immune and Inflammatory Disorders: Therapeutic Interventions

Ricklin

Lambris

2013

The Journal of Immunology

205

230

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With the awareness that immune-inflammatory crosstalk is at the heart of many disorders, the desire for novel immunomodulatory strategies in the therapy of such diseases has grown dramatically. As a prime initiator and important modulator of immunological and inflammatory processes, the complement system has emerged as an attractive target for early and upstream intervention in inflammatory diseases and has moved into the spotlight of drug discovery. While prevalent conditions such as age-related macular degeneration have attracted the most attention, the diverse array of complement-mediated pathologies, with distinct underlying mechanisms, demands a multifaceted arsenal of therapeutic strategies. Fortunately, efforts in recent years have not only introduced the first complement inhibitors to the clinic but also filled the pipelines with promising candidates. With a focus on immunomodulatory strategies, this review discusses complement-directed therapeutic concepts and highlights promising candidate molecules.

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Section: The Therapeutic Arsenal To Tackle Complement-related Diseasesmentioning

confidence: 99%

Complement in Immune and Inflammatory Disorders: Therapeutic Interventions

Ricklin

Lambris

2013

The Journal of Immunology

205

230

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“…Besides plasma donated inhibitors or antibodies, small molecules are also another way to target and inhibit C1s. Potential small molecule inhibitors have been found [ 27 , 30 , 31 ], modified [ 32 , 33 ] and PEGylated [ 34 ] to circumvent shortcomings.…”

Section: Introductionmentioning

confidence: 99%

“…Computers have been growing in power and utility at an exponential rate and can now start to complement traditional design/search methodologies for new drug candidates [ 35 ]. In fact, computational approaches were used previously to identify how small molecules docked into C1s [ 31 , 32 , 33 , 34 ] but not to identify new leads. Researchers have used virtual high-throughput screening to identify leads for other factors in the complement system [ 36 ].…”

Section: Introductionmentioning

confidence: 99%

Pharmaceutical Machine Learning: Virtual High-Throughput Screens Identifying Promising and Economical Small Molecule Inhibitors of Complement Factor C1s

2018

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When excessively activated, C1 is insufficiently regulated, which results in tissue damage. Such tissue damage causes the complement system to become further activated to remove the resulting tissue damage, and a vicious cycle of activation/tissue damage occurs. Current Food and Drug Administration approved treatments include supplemental recombinant C1 inhibitor, but these are extremely costly and a more economical solution is desired. In our work, we have utilized an existing data set of 136 compounds that have been previously tested for activity against C1. Using these compounds and the activity data, we have created models using principal component analysis, genetic algorithm, and support vector machine approaches to characterize activity. The models were then utilized to virtually screen the 72 million compound PubChem repository. This first round of virtual high-throughput screening identified many economical and promising inhibitor candidates, a subset of which was tested to validate their biological activity. These results were used to retrain the models and rescreen PubChem in a second round vHTS. Hit rates for the first round vHTS were 57%, while hit rates for the second round vHTS were 50%. Additional structure–property analysis was performed on the active and inactive compounds to identify interesting scaffolds for further investigation.

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“…147 Nonetheless, a series of pegylated biphenyl sulfonyl thiophene derivatives have demonstrated potent and selective C1s inhibition together with a good pharmacokinetic profile in vivo. 159 Peptidomimetic inhibitors of C1r and C1s have also been developed based on known thrombin inhibitors. The original BASF patent (WO200061608-A2/US6683055-B1) described over 800 compounds but provided C1r/C1s enzyme inhibition data for only 50 examples.…”

Section: Complement Proteins As Targetsmentioning

confidence: 99%

Chemical Approaches to Modulating Complement-Mediated Diseases

Iyer

Reid

et al. 2017

J. Med. Chem.

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Numerous diseases are driven by chronic inflammation, placing major burdens on our health systems. Controlling inflammation is an important preventative and therapeutic goal. Over 40 "Complement" proteins are produced in blood or on cell surfaces through activation of the Complement protein network mainly by infection or injury. These proteins complement immune cells and antibodies to identify, tag, destroy, and eliminate pathogens and infected or damaged cells and repair tissues. If the inflammatory stimulus is not removed by localized acute immune responses, Complement activation may be prolonged or misdirected to healthy cells, and chronic inflammation can lead to inflammatory or autoimmune diseases. The formation, structures, and interplay between Complement proteins are complex, and this has limited our detailed understanding of their roles and importance in physiology and disease. With the availability of new structures for Complement proteins, new knowledge of how they function, and new modulators of Complement-driven signaling, there are also new opportunities to intervene in Complement-mediated disease. Small molecule and peptide-based drug leads, identified as clues for Complement-directed therapeutic development, are assembled here together with the available evidence for their efficacy in cellular and animal models of human inflammatory disease and in some human clinical conditions.

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Design and synthesis of polyethylene glycol-modified biphenylsulfonyl-thiophene-carboxamidine inhibitors of the complement component C1s

Cited by 7 publications

References 15 publications

Complement in Immune and Inflammatory Disorders: Therapeutic Interventions

Complement in Immune and Inflammatory Disorders: Therapeutic Interventions

Pharmaceutical Machine Learning: Virtual High-Throughput Screens Identifying Promising and Economical Small Molecule Inhibitors of Complement Factor C1s

Chemical Approaches to Modulating Complement-Mediated Diseases

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