Designed Macrocyclic Kinase Inhibitors

Poulsen, Anders; William, Anthony D.; Dymock, Brian

doi:10.1039/9781782623113-00141

Cited by 7 publications

(3 citation statements)

References 107 publications

(116 reference statements)

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“…At the outset, the design strategy involved optimization of compound 4 for CNS penetration by deconstructing the solvent-exposed substituents and attempting to regain binding affinity via macrocyclization of the resulting simplified pharmacophore (i.e., analog 8 , Figure ). Conceptually, this approach relied on the observation that the phenyl group and triazole ring are in close spatial proximity and on the insight that macrocyclic structures typically have reduced conformational freedom, which can result in ligands with increased binding affinity …”

Section: Resultsmentioning

confidence: 99%

Rational Design and Optimization of a Novel Class of Macrocyclic Apoptosis Signal-Regulating Kinase 1 Inhibitors

et al. 2019

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Structural analysis of a known apoptosis signal-regulating kinase 1 (ASK1) inhibitor bound to its kinase domain led to the design and synthesis of the novel macrocyclic inhibitor 8 (cell IC50 = 1.2 μM). The profile of this compound was optimized for CNS penetration following two independent strategies: a rational design approach leading to 19 and a parallel synthesis approach leading to 26. Both analogs are potent ASK1 inhibitors in biochemical and cellular assays (19, cell IC50 = 95 nM; 26, cell IC50 = 123 nM) and have moderate to low efflux ratio (ER) in an MDR1-MDCK assay (19, ER = 5.2; 26, ER = 1.5). In vivo PK studies revealed that inhibitor 19 had moderate CNS penetration (K puu = 0.17) and analog 26 had high CNS penetration (K puu = 1.0).

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Section: Resultsmentioning

confidence: 99%

Rational Design and Optimization of a Novel Class of Macrocyclic Apoptosis Signal-Regulating Kinase 1 Inhibitors

et al. 2019

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“…Recently, macrocyclic fragments have been actively studied for this purpose. They offer fixed spatial separation of the binding groups to get variety of ligands toward different molecules to be recognized (Poulsen et al, 2015; Imran et al, 2018) (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Modification of Oligo- and Polylactides With Macrocyclic Fragments: Synthesis and Properties

et al. 2019

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Products of lactic acid polycondensation (poly- and oligolactic acids) are widely used as packaging materials, drug delivery agents, implants etc. Variety of their applications is caused by a number of practically important properties, e.g., biocompatibility and biodegradability, non-toxicity, and mechanical durability. Modification of these polymers with different additives allows improving their properties and extending future applications. In this manner, stability toward degradation, recognition of some substrates, extended thermal stability etc. can be improved. Macrocyclic compounds are promising candidates as modifiers. They are able to provide polymer materials with additional binding sites, impart certain orientation to spatial arrangement of polymer chains, change hydrophilic-lipophilic balance, and redox properties. The latter one can be used for assembling various electrochemical sensors and biosensors that combine steric discrimination of the analytes caused by oligolactides and highly sensitive response to their quantities caused by redox labels introduced. Different composite materials based on oligolactides as matrices for such redox labels were described in the assemblies of biosensors for drugs, pesticides, and antioxidants detection. In this mini-review, methods for the synthesis of the lactic acid oligomers and those modified with the macrocyclic fragments (porphyrin, cyclodextrin, and cyclophane) have been described. The effects of modifiers on complexation, thermal, and aggregation properties of materials are described. Analytical performance of oligolactide based sensors and biosensors has been considered with particular emphasis to the mechanism of signal generation.

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“…Reactions are promoted by a molybdenum monoaryloxide pyrrolide complex and afford products in up to 73 percent yield and >98:2 E:Z ratio. Utility is highlighted by application to preparation of the twelve-membered ring antibiotic recifeiolide 12,13 and the eighteen-membered ring Janus kinase 2/Fms-like tyrosine kinase-3 (JAK2/FLT3) inhibitor pacritinib 14,15 the Z isomer of which has lower potency than the E 16 . The eighteen-membered ring moiety of pacritinib, a potent in vivo anti-cancer agent in advanced clinical trials for treatment of lymphoma and myelofibrosis, was prepared by an RCM carried out at 20 times higher concentration than when a ruthenium carbene was employed (0.02 vs. 0.001 M; 73% yield, 92% E ).…”

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confidence: 99%

Kinetically E-selective macrocyclic ring-closing metathesis

Shen

Nguyen

Koh

et al. 2017

Nature

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Macrocyclic compounds are central to discovery of new drugs but their preparation is often challenging because of the energy barrier required for bringing together and fusing the two ends of an acyclic precursor1. Ring-closing metathesis (RCM) 2,3,4 is a catalytic process that has allowed access to countless biologically active macrocyclic organic molecules even on large scale (up to 200 kilograms)5. The potency of a macrocyclic compound can depend on the stereochemistry of its alkene, or one isomer might be needed for subsequent stereoselective modification (e.g., dihydroxylation6). Still, while kinetically controlled Z-selective RCM reactions have been reported7,8,9,10, the only available olefin metathesis approach for accessing macrocyclic E olefins entails selective removal of the Z component of a stereoisomeric mixture by ethenolysis10, sacrificing substantial quantities of material if E/Z ratios are near unity. Use of ethylene can also cause adventitious olefin isomerization, a particularly serious problem when the E alkene is energetically less favored. Here, we show that dienes containing an E-alkenyl–B(pinacolato) group, widely used in catalytic cross-coupling11, possess the requisite electronic and steric attributes to allow them to be converted stereoselectively to E macrocyclic alkenes. Reactions are promoted by a molybdenum monoaryloxide pyrrolide complex and afford products in up to 73 percent yield and >98:2 E:Z ratio. Utility is highlighted by application to preparation of the twelve-membered ring antibiotic recifeiolide12,13 and the eighteen-membered ring Janus kinase 2/Fms-like tyrosine kinase-3 (JAK2/FLT3) inhibitor pacritinib14,15 the Z isomer of which has lower potency than the E16. The eighteen-membered ring moiety of pacritinib, a potent in vivo anti-cancer agent in advanced clinical trials for treatment of lymphoma and myelofibrosis, was prepared by an RCM carried out at 20 times higher concentration than when a ruthenium carbene was employed (0.02 vs. 0.001 M; 73% yield, 92% E).

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Designed Macrocyclic Kinase Inhibitors

Cited by 7 publications

References 107 publications

Rational Design and Optimization of a Novel Class of Macrocyclic Apoptosis Signal-Regulating Kinase 1 Inhibitors

Rational Design and Optimization of a Novel Class of Macrocyclic Apoptosis Signal-Regulating Kinase 1 Inhibitors

Modification of Oligo- and Polylactides With Macrocyclic Fragments: Synthesis and Properties

Kinetically E-selective macrocyclic ring-closing metathesis

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