Design, Synthesis, and Characterization of I-BET567, a Pan-Bromodomain and Extra Terminal (BET) Bromodomain Oral Candidate.

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.

Synthesis of imprinted beads by aqueous suspension polymerisation for chiral recognition of antihistamines.

A novel non-stabilised aqueous suspension polymerisation methodology for the preparation of spherical molecularly imprinted polymers is described with chlorpheniramine (CP), d-chlorpheniramine (d-CP), brompheniramine (BP) and d-brompheniramine (d-BP) as the templates, respectively. Using this rapid and simple technique, controlled polymer beads in the low micron range with narrow size distributions were generated by photo-polymerisation. The use of agitation speed as a method of controlling bead size distribution was demonstrated. Enantioselective properties of the imprinted beads were examined and the polymers prepared using d-chlorpheniramine and d-brompheniramine were capable of discriminating between the enantiomers of the template. Cross-selectivity studies were performed by batch rebinding with the influence of template size and functional group orientation of analytes on the recognition properties of the imprinted polymers investigated. Physical characteristics of all polymers were studied by nitrogen sorption porosimetry, particle size analysis and scanning electron microscopy (SEM) in order to gain an insight into the role of such properties on retention behaviour.

The use of FTIR and NMR spectroscopies to study prepolymerisation interactions in nitrogen heterocycles.

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.