Molecularly Imprinted Polymers (MIPs) against S-ibuprofen were synthesised using a tailor made functional monomer, 2-acrylamido-4-methylpyridine, following extensive pre-polymerisation studies of template-monomer complexation. An apparent association constant of 340 AE 22 M À1 was calculated that was subsequently corrected to account for dimerisation of ibuprofen (K dim ¼ 320 AE 95 M À1) resulting in an intrinsic association constant of 715 AE 16 M À1 , consistent with previously reported values. Using the synthesised imprinted polymer as a stationary phase, complete resolution of a racemic mixture of ibuprofen was achieved in predominantly aqueous mobile phases. An imprinting factor of 10 was observed, and was found to be in agreement with the difference in the average number of binding sites between MIP and blank polymers, calculated by staircase frontal chromatography. The imprinted polymers exhibited enhanced selectivity for the templated drug over structurally related NSAIDs. When applied as sorbents in solid-phase extraction of ibuprofen from commercial tablets, urine and blood serum samples, recoveries up to 92.2% were achieved.
Through regulation of the epigenome,
the bromodomain and extra
terminal (BET) family of proteins represent important therapeutic
targets for the treatment of human disease. Through mimicking the
endogenous N-acetyl-lysine group and disrupting the
protein–protein interaction between histone tails and the bromodomain,
several small molecule pan-BET inhibitors have progressed to oncology
clinical trials. This work describes the medicinal chemistry strategy
and execution to deliver an orally bioavailable tetrahydroquinoline
(THQ) pan-BET candidate. Critical to the success of this endeavor
was a potency agnostic analysis of a data set of 1999 THQ BET inhibitors
within the GSK collection which enabled identification of appropriate
lipophilicity space to deliver compounds with a higher probability
of desired oral candidate quality properties. SAR knowledge was leveraged
via Free–Wilson analysis within this design space to identify
a small group of targets which ultimately delivered I-BET567 (27), a pan-BET candidate inhibitor that demonstrated efficacy
in mouse models of oncology and inflammation.
A detailed investigation into the functional groups responsible for the formation of a noncovalent complex between 2-aminopyridine (template) and methacrylic acid (functional monomer) has been carried out using FTIR spectroscopy and confirmed by (1)H NMR spectroscopic data. The approach adopted to confirm the mechanism of interaction was the analysis of the template plus the structurally similar 2-methylaminopyridine and 2-dimethylaminopyridine. A 1:1 stoichiometry of complexation was determined by Job plot analysis following titration, with FTIR results complementing those of the (1)H NMR study. The strength of interaction between 2-aminopyridine and the functional monomer measured through band shifts by FTIR spectroscopy was compared with such interactions for the isomers 3- and 4-aminopyridine. This comparison identified a clear correlation between template pK(a), degree of interaction and subsequent nonspecific binding in the nonimprinted polymer. Using FTIR spectroscopy it was also possible to observe the effect of temperature on the prepolymerisation solution. IR spectra showed that lower temperatures led to more stabilized interactions of the hydrogen-bonded complex. The potential advantages of FTIR spectroscopy compared with (1)H NMR spectroscopy in studying prepolymerisation solutions have been identified.
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