Medicines discovery for auditory disorders: Challenges for industry.

Currently, no approved medicines are available for the prevention or treatment of hearing loss. Pharmaceutical industry productivity across all therapeutic indications has historically been disappointing, with a 90% chance of failure in delivering a marketed drug after entering clinical evaluation. To address these failings, initiatives have been applied in the three cornerstones of medicine discovery: target selection, clinical candidate selection, and clinical studies. These changes aimed to enable data-informed decisions on the translation of preclinical observations into a safe, clinically effective medicine by ensuring the best biological target is selected, the most appropriate chemical entity is advanced, and that the clinical studies enroll the correct patients. The specific underlying pathologies need to be known to allow appropriate patient selection, so improved diagnostics are required, as are methodologies for measuring in the inner ear target engagement, drug delivery and pharmacokinetics. The different therapeutic strategies of protecting hearing or preventing hearing loss versus restoring hearing are reviewed along with potential treatments for tinnitus. Examples of current investigational drugs are discussed to highlight key challenges in drug discovery and the learnings being applied to improve the probability of success of launching a marketed medicine.

4-Phenyl-7-azaindoles as potent, selective and bioavailable IKK2 inhibitors demonstrating good in vivo efficacy.

The lead optimization of a series of potent azaindole IKK2 inhibitors is described. Optimization of the human whole blood activity and selectivity over IKK1 in parallel led to the discovery of 16, a potent and selective IKK2 inhibitor showing good efficacy in a rat model of neutrophil activation.

4-Phenyl-7-azaindoles as potent and selective IKK2 inhibitors.

The synthesis and SAR of a novel series of IKK2 inhibitors are described. Modification around the hinge binding region of the 7-azaindole led to a series of potent and selective inhibitors with good cellular activity.

Enantioselective partial reduction of 2,5-disubstituted pyrroles via a chiral protonation approach.

[reaction: see text] The partial reduction of 2,5-pyrrole diester 1 followed by enantioselective protonation in situ to furnish synthetically useful building blocks is described. An enantiomeric excess of up to 74% was achieved using (-)-ephedrine and related analogues as chiral proton sources. The pyrroline product obtained could be recrystallized to give enantiomerically pure material.

Rearrangement of pyrrolines derived from the Birch reduction of electron-deficient pyrroles: radical ring-expansion to substituted tetrahydropyridines.

Access to the synthetically important tetrahydropyridine motif has been achieved by radical rearrangement of pyrrolines obtained from the Birch reduction of electron-deficient pyrroles.

Flexibility in the partial reduction of 2,5-disubstituted pyrroles: application to the synthesis of DMDP.

[reaction: see text] The partial reduction of electron-deficient 2,5-disubstituted pyrroles has been developed into a flexible procedure that gives control of relative stereochemistry by variation of the reduction conditions. After the reaction, the pyrroline products were dihydroxylated at C-3,4 to give either the cis or trans isomers; this flexibility means that a variety of polyhydroxylated pyrrolidines can be prepared in a short sequence. Finally, this method was applied to a synthesis of the naturally occurring glycosidase inhibitor DMDP.