Optimisation of a novel series of potent and orally bioavailable azanaphthyridine SYK inhibitors

Garton, Neil; Barker, Michael D.; Davis, Rob P.; Douault, Clement; Hooper‐Greenhill, Edward; Jones, Emma; Lewis, Huw D.; Liddle, John; Lugo, Dave; McCleary, Scott; Preston, Alex; Ramírez-Molina, César; Neu, Margarete; Shipley, Tracy J.; Somers, Don O.; Watson, Robert J.; Wilson, David M.

doi:10.1016/j.bmcl.2016.08.070

Cited by 9 publications

(9 citation statements)

References 18 publications

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“…It is however, extremely difficult to estimate whether the selected functional group replacements or the scaffold‐expansions have the ideally suited properties for the given binding site. This decision concerns properties, such as the correct placement of a charged or strongly polarized group influencing the overall distribution of electron density across the attached moiety or the adjustment of an optimal p K a value affecting protonation and bioavailability [9–12] . Furthermore, the parent scaffold, to which the bioisosteric replacement is chemically connected, will also impose constraints depending on the chemical connectivity of the molecule.…”

Section: Figurementioning

confidence: 99%

“…This decision concerns properties, such as the correct placement of a charged or strongly polarized group influencing the overall distribution of electron density across the attached moiety or the adjustment of an optimal pK a value affecting protonation and bioavailability. [9][10][11][12] Furthermore, the parent scaffold, to which the bioisosteric replacement is chemically connected, will also impose constraints depending on the chemical connectivity of the molecule. These constraints can be of steric or electronic nature.…”

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confidence: 99%

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Fragment Binding to Kinase Hinge: If Charge Distribution and Local pK_a Shifts Mislead Popular Bioisosterism Concepts

et al. 2020

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Medicinal-chemistry optimization follows strategies replacing functional groups and attaching larger substituents at a promising lead scaffold. Well-established bioisosterism rules are considered, however, it is difficult to estimate whether the introduced modifications really match the required properties at a binding site. The electron density distribution and pK a values are modulated influencing protonation states and bioavailability. Considering the adjacent H-bond donor/ acceptor pattern of the hinge binding motif in a kinase, we studied by crystallography a set of fragments to map the required interaction pattern. Unexpectedly, benzoic acid and benzamidine, decorated with the correct substituents, are totally bioisosteric just as carboxamide and phenolic OH. A mono-dentate pyridine nitrogen out-performs bi-dentate functionalities. The importance of correctly designing pK a values of attached functional groups by additional substituents at the parent scaffold is rendered prominent.

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Section: Figurementioning

confidence: 99%

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Fragment Binding to Kinase Hinge: If Charge Distribution and Local pK_a Shifts Mislead Popular Bioisosterism Concepts

et al. 2020

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“…Die Beurteilung dieser Auswahl betrifft Eigenschaften wie die korrekte Platzierung einer geladenen oder stark polarisierten Gruppe, die die Gesamtverteilung der Elektronendichte über die angefügte Gruppe beeinflusst oder die Einstellung eines optimalen p K a ‐Wertes bestimmt. Dies legt die Protonierung des Liganden fest und beeinflusst dessen Bioverfügbarkeit [9–12] . Darüber hinaus wird auch das Grundgerüst, an das die bioisostere Austauschgruppe chemisch gebunden wird, je nach der Chemie zum Erstellen der Verknüpfung einen Einfluss nehmen.…”

Section: Figureunclassified

“…Dies legt die Protonierung des Liganden fest und beeinflusst dessen Bioverfügbarkeit. [9][10][11][12] Darüber hinaus wird auch das Grundgerüst, an das die bioisostere Austauschgruppe chemisch gebunden wird, je nach der Chemie zum Erstellen der Verknüpfung einen Einfluss nehmen. Diese Einflüsse kçnnen sterischer wie elektronischer Natur sein.…”

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Fragment‐Bindung an die Kinase‐Scharnier‐Region: Wenn Ladungsverteilung und lokale pK_a‐Verschiebungen etablierte Bioisosterie‐Konzepte fehlleiten

et al. 2020

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Die medizinisch-chemische Optimierung folgt einer Strategie, funktionelle Gruppen zu ersetzen und grçßere Substituenten an ein vielversprechendes Leitstrukturgerüst anzufügen. Wohl etablierte Bioisosterie-Regeln werden berücksichtigt, dennoch ist es schwierig abzuschätzen, ob die durchgeführten Modifikationen auch wirklich den Anforderungen einer Bindestelle gerecht werden. Die Elektronendichteverteilung und die pK a-Werte der Liganden werden moduliert und beeinflussen so Protonierungszustände und Bioverfügbarkeiten. Unter Berücksichtigung des benachbarten H-Brücken-Donor/Akzeptor-Musters des Scharnierbindungsmotivs ("Hinge-Region") einer Kinase untersuchten wir kristallographisch eine Reihe von Fragmenten, um zu sehen, ob sie das erforderliche Interaktionsmuster erwidern kçnnen. Unerwarteterweise sind Benzoesäure und Benzamidin, mit den richtigen Substituenten dekoriert, ebenso wie ein Carboxamid oder eine phenolische OH-Gruppe vçllig bioisoster. Ein einzähniger Pyridinstickstoff übertrifft sogar zweizähnige Funktionalitäten am Liganden. Die Bedeutung der korrekten Einstellung von pK a-Werten der angefügten funktionellen Gruppen am Liganden durch zusätzliche Substituenten am Molekülgerüst wird damit offensichtlich.

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“…GSK2646264 is a small molecule inhibitor of SYK recently discovered at GlaxoSmithKline (Barker et al, ) as part of an extension to previous efforts to identify oral SYK inhibitors (Garton et al, ; Liddle et al, ). In vitro, GSK2646264 demonstrated consistent potency across assays relevant to the mechanism of SYK inhibition including an IgE stimulated LAD2 assay and good selectivity over a range of closely related kinases with at least 30‐fold selectivity over 10 other unrelated kinases (Barker et al, ).…”

Section: Introductionmentioning

confidence: 99%

GSK2646264, a spleen tyrosine kinase inhibitor, attenuates the release of histamine in ex vivo human skin

Molina

Falkencrone²,

Skov³

et al. 2019

British J Pharmacology

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Background and Purpose: Chronic spontaneous urticaria presents as a heterogeneous syndrome characterised by wheals, angioedema, or both for greater than 6 weeks. Spleen tyrosine kinase mediates allergen-induced mast cell degranulation via the IgE signalling pathway, a central component of wheal formation and inflammation. In this study, we investigated the effects of perfused or topically administered GSK2646264 on IgE-mediated histamine release from mast cells in an ex vivo human skin model. Experimental Approach: Using a novel SkiP device, ex vivo human skin from mastectomy surgeries was challenged with anti-IgE, complement 5a (C5a), and buffer to induce histamine release from skin mast cells. Histamine was collected via microdialysis fibres and measured fluorometrically. GSK2646264 was delivered via perfusion either using microdialysis fibres or topically in a cream. Drug concentrations in the skin were measured by LC-MS, and a pharmacokinetic/ pharmacodynamic (PK/PD) relationship developed.Key Results: Perfused GSK2646264 significantly inhibited anti-IgE (but not C5a)induced histamine release in a concentration-dependent manner. The 0.5, 1, and 3% cream delivered GSK2646264 to the dermis above the IC 90 and dosedependently attenuated anti-IgE-induced histamine release.Conclusions and Implications: GSK2646264 administered topically or direct to the dermis blocked histamine release from in situ skin mast cells. A PK/PD relationship curve suggests that dermal concentrations above 6.8 μM should lead to approximately 90% inhibition of histamine release from skin mast cells following activation of the Fc fragment of IgE receptor 1a, implicating a potential use for the compound in skin mast cell diseases such as urticaria.

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Optimisation of a novel series of potent and orally bioavailable azanaphthyridine SYK inhibitors

Cited by 9 publications

References 18 publications

Fragment Binding to Kinase Hinge: If Charge Distribution and Local pK_a Shifts Mislead Popular Bioisosterism Concepts

Fragment Binding to Kinase Hinge: If Charge Distribution and Local pK_a Shifts Mislead Popular Bioisosterism Concepts

Fragment‐Bindung an die Kinase‐Scharnier‐Region: Wenn Ladungsverteilung und lokale pK_a‐Verschiebungen etablierte Bioisosterie‐Konzepte fehlleiten

GSK2646264, a spleen tyrosine kinase inhibitor, attenuates the release of histamine in ex vivo human skin

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Optimisation of a novel series of potent and orally bioavailable azanaphthyridine SYK inhibitors

Cited by 9 publications

References 18 publications

Fragment Binding to Kinase Hinge: If Charge Distribution and Local pKa Shifts Mislead Popular Bioisosterism Concepts

Fragment Binding to Kinase Hinge: If Charge Distribution and Local pKa Shifts Mislead Popular Bioisosterism Concepts

Fragment‐Bindung an die Kinase‐Scharnier‐Region: Wenn Ladungsverteilung und lokale pKa‐Verschiebungen etablierte Bioisosterie‐Konzepte fehlleiten

GSK2646264, a spleen tyrosine kinase inhibitor, attenuates the release of histamine in ex vivo human skin

Contact Info

Product

Resources

About

Fragment Binding to Kinase Hinge: If Charge Distribution and Local pK_a Shifts Mislead Popular Bioisosterism Concepts

Fragment Binding to Kinase Hinge: If Charge Distribution and Local pK_a Shifts Mislead Popular Bioisosterism Concepts

Fragment‐Bindung an die Kinase‐Scharnier‐Region: Wenn Ladungsverteilung und lokale pK_a‐Verschiebungen etablierte Bioisosterie‐Konzepte fehlleiten