Probing the Subpockets of Factor Xa Reveals Two Binding Modes for Inhibitors Based on a 2-Carboxyindole Scaffold:  A Study Combining Structure-Activity Relationship and X-ray Crystallography

Nazaré, Marc; Will, David W.; Matter, Hans; Schreuder, Herman; Ritter, Kurt; Urmann, Matthias; Essrich, M.; Bauer, Armin; Wagner, Michael R.; Czech, Jörg; Lorenz, Martin; Laux, Volker; Wehner, Volkmar

doi:10.1021/jm0490540

Cited by 115 publications

(170 citation statements)

References 38 publications

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“…[48][49][50] Matter et al reported two series of halogenated inhibitors of serine protease factor Xa and showed that organic chlorines/bromines in both series are favorably in close contact with the phenyl ring of Tyr228 at the back wall of the protease S1 pocket. 51,52 Rivaroxaban, a factor Xa inhibitor, contains an aromatic carbon-chlorine moiety and is buried inside the S1 pocket of factor Xa (Fig. 4).…”

Section: Discussionmentioning

confidence: 99%

Halogen bonding for the design of inhibitors by targeting the S1 pocket of serine proteases

et al. 2018

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Halogen bonding (or X bonding) has attracted increasing interest due to its significant role in molecular recognition in biological systems. Trypsin-like serine proteases have many physiological and pathophysiological functions. There is therefore extensive interest in generating specific inhibitors for pharmacological intervention in their enzymatic activity. We study here if it is possible to use halogenated compounds as the P1 group to bind to the S1 specificity pocket of trypsin-like serine proteases to avoid the low bioavailability of the amidine or guanidine P1 group that is typically used in many inhibitors. We used 4-chlorobenzylamine (ClBA), 4-bromobenzylamine (BrBA) and 4-iodobenzylamine (IBA) as probes to test their binding modes to a trypsin-like serine protease, urokinasetype plasminogen activator (uPA), which has been recognized as a marker for breast cancer and an important target for inhibitor development. The results showed that these compounds inhibited uPA with stronger efficacies compared with their non-halogenated analogues. We also determined the highresolution crystal structures of uPA in complex with BrBA and IBA, respectively. The structures revealed that BrBA bound to the S1 pocket of uPA via halogen bonds, but IBA did not make halogen bonds with uPA, demonstrating that the iodine may not be the best choice as a target moiety for serine proteases.These results advocate halogen bonding, especially bromine bonding, as an efficient strategy for the future design of novel inhibitors against trypsin-like serine proteases to provide strong potency and promote bioavailability.

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Section: Discussionmentioning

confidence: 99%

Halogen bonding for the design of inhibitors by targeting the S1 pocket of serine proteases

et al. 2018

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“…As expected, the highest yields were obtained for the more activated substrates, 2b-c (Table 6, entries 2-3). However, even for the non-activated substrates 4k-l, the respective indoles 2k-l were obtained, albeit in low yields (Table 6, entries [11][12]. Likewise, α-anilinoacetophenones 4o-p satisfactorily reacted to give indoles 2n-o, respectively (Table 6, entries [14][15].…”

Section: Preparation Of Indoles 1a-pmentioning

confidence: 97%

“…7 In particular, 2-carboxyindoles are enzyme inhibitors, such as hyaluronidase, 8 tubuline polymerization, 9 HIV-1 integrase, 10 human cytosolic phospholipase A 2  11 and factor Xa. 12 In the case of 3-aminoindoles and cyclic-fused analogues, they have been found to be effective as anticancer, 13 antiplasmodial and cytotoxic agents. 14 As a consequence of these relevant activities and applications, a great number of synthetic routes leading to 2-substituted indoles have been described in the literature.…”

Section: Introductionmentioning

confidence: 99%

Iodine-mediated one-pot synthesis of indoles and 3-dimethylaminoindoles via annulation of enaminones

Jerezano¹,

Labarrios²,

Jiménez³

et al. 2013

Arkivoc

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The synthesis of 2-carbonylindoles was achieved via a iodine-mediated cyclization of the corresponding enaminone precursors, which were formed by reaction of the -arylaminomethylene carbonyl derivatives with N,N′-dimethylformamide dimethyl acetal (DMFDMA). An alternative and more efficient procedure consisted of a similar cyclization of the enaminones, but under solvent-free and grinding reaction conditions. In another iodine-promoted procedure, 2-carbonyl-3-dimethylaminoindoles were synthesized via a one-pot cascade reaction between the -arylaminomethylene carbonyl derivative and DMFDMA.

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“…The first component involved a Coulombic interaction between positive and negative charges (so-called ion pairing), whereas the second reflected a bidentate hydrogen bond. 52 Elimination of either of these interactions increased the K i by one to two orders of magnitude. 52 Building on this information, the amidine group in the P1 position was replaced with nonbasic moieties in an attempt to increase oral bioavailability.…”

Section: Development Of Synthetic Oral Direct Fxa Inhibitorsmentioning

confidence: 99%

“…52 Elimination of either of these interactions increased the K i by one to two orders of magnitude. 52 Building on this information, the amidine group in the P1 position was replaced with nonbasic moieties in an attempt to increase oral bioavailability. 53 Various linker or P4 elements were then added to overcome the subsequent loss in potency by maximizing interactions at the S4 site.…”

Section: Development Of Synthetic Oral Direct Fxa Inhibitorsmentioning

confidence: 99%

Oral Direct Factor Xa Inhibitors

Fredenburgh

Weitz

2012

Circulation Research

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Vitamin K antagonists, such as warfarin, have been the mainstay of oral anticoagulation for many decades. Although effective, warfarin has numerous limitations, including a variable dose requirement from patient to patient because of differences in dietary vitamin K intake, common genetic polymorphisms, and multiple drug interactions that affect its pharmacodynamics and metabolism. Consequently, warfarin requires frequent monitoring to ensure that a therapeutic anticoagulant effect has been achieved because excessive anticoagulation can lead to bleeding, and because insufficient anticoagulation can result in thrombosis. Such monitoring is burdensome for patients and physicians and is costly for the health care system. These limitations have prompted the development of new oral anticoagulants that target either factor Xa or thrombin. Although the path to the development of these drugs has been long, the new drugs are at least as effective and safe as warfarin, but they streamline clinical care because they can be administered in fixed doses without routine coagulation monitoring. This article focuses on rivaroxaban, apixaban, and edoxaban, the oral factor Xa inhibitors in the most advanced stages of development. After 20 years of discovery research, these agents are already licensed for several indications. Thus, the long path to finding replacements for warfarin has finally reached fruition. Therefore, development of the oral factor Xa inhibitors represents a translational science success story.

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Probing the Subpockets of Factor Xa Reveals Two Binding Modes for Inhibitors Based on a 2-Carboxyindole Scaffold: A Study Combining Structure-Activity Relationship and X-ray Crystallography

Cited by 115 publications

References 38 publications

Halogen bonding for the design of inhibitors by targeting the S1 pocket of serine proteases

Halogen bonding for the design of inhibitors by targeting the S1 pocket of serine proteases

Iodine-mediated one-pot synthesis of indoles and 3-dimethylaminoindoles via annulation of enaminones

Oral Direct Factor Xa Inhibitors

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