Invacaftor discovery

Cystic fibrosis (CF) is a lethal genetic disease that affects approximately 70000 patients worldwide. The story of the discovery of Ivacaftor starts with a specialised high content screening campaign, which yielded a fairly average ‘looking’ hit. This modern discovery effort fully describes the complete work up and optimisation of a hit into a candidate drug – this is quite unusual, as many programs end up breaking down the work into several publications. On note is the full and detailed characterisation of the hit compound (about 2 uM), which put the project in a strong position. At this point a hit with a relatively low molecular weight of 368 and cLogP of 2.9, and well understood functional activity, was very attractive. The initial SAR exploration is excellent: a handful of well thought out compounds showed the binding mode of the series, and which tautomer form was key to binding – take note. The second exploration found a new hydrogen bond to explore and optimise, in the form of an indole. Take note again the team fully characterised this compound, and found excellent selectivity against a panel of protein targets, but poor solubility and sub-optimal pharmacokinetics – this again placed the project in a strong position. Next to understand the poor solubility the team proposed and modelled potential intramolecular hydrogen bonds and a planar structure, which were confirmed by a single crystal x-ray determinations – this is the definitive method. Efforts to disrupt the intramolecular H-bonds and planarity did find tert-butyl groups could be added. This approach would normally yield a molecule high in lipophilicity an unlikely to have good solubility. However, work to find an iso-steres to indole found a phenol group could be used. Normally a classic med-chem change is phenol to indole, but this is the reverse. Phenols are not normally desirable as they undergo secondary metabolism resulting in short half-life, but flanked with a t-butyl group this clearly does not occur as PK was good for this combination of groups.

Ivacaftor – Discovery of N-(2,4-Di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (VX-770, Ivacaftor), a Potent and Orally Bioavailable CFTR Potentiators.

J. Med. Chem. 2014, 57, 23, 9776–9795.

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