A program aimed at discovery of small molecule PCSK9 translation inhibitors will be described. This relatively new frontier of targeting of the human ribosome is an unprecedented therapeutic modality with a genome-wide selectivity challenge. A single hit compound, PF-00932239, was discovered through an unbiased high-throughput screening effort. Library and singleton work revealed that compounds with subtle structural changes yielded significant changes in pharmacology. Subsequent efforts led to identification of the lead compound PF-06446846, which demonstrated PCSK9 and cholesterol lowering in rats. Compounds with improved toleration were ultimately achieved by identification of liver-targeted drug candidates. The key to this concept relied on pharmacologically active zwitterions designed to be retained in the liver. Oral delivery of the poorly permeable zwitterions was solved by identification of a regio- and stereochemically specific tetrazole prodrug (PF-06815345) that was susceptible to cleavage by carboxylesterase 1. Oral dosing of PF-06815345 provided enhanced liver delivery of the zwitterion relative to earlier generation prodrug molecules in non-human primates. Drug fraction delivered to the liver could be quantified in an oral positron emission tomography study. In an effort to prepare sufficient quantities of PF-06815345 for clinical evaluation, a multikilogram synthesis was developed that relied on cross-coupling of a boronic ester and a base-sensitive tetrazole prodrug fragment. The initial route featured a safe method to prepare 5-(4-iodo-1-methyl-1<i>H</i>-pyrazol-5-yl)-2<i>H</i>-tetrazole and its hemiaminal prodrug but required chromatography on chiral support to access the required prodrug regio- and stereoisomer. Enablement of a more efficient route led to development of a tin-mediated tetrazole alkylation followed by biocatalytic resolution to provide the chiral prodrug fragment. This new approach doubled the overall yield, removed all chromatographic purifications and provided ample material for clinical studies.

Discovery of small molecule inhibitors of PCSK9. Part 1: Medicinal chemistry progression

256th National Meeting (2018)

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