Assessing the impact of expert knowledge on ICH M7 (Q)SAR predictions. Is expert review still needed?

The ICH M7 (R1) guideline recommends the use of complementary (Q)SAR models to assess the mutagenic potential of drug impurities as a state-of-the-art, high-throughput alternative to empirical testing. Additionally, it includes a provision for the application of expert knowledge to increase prediction confidence and resolve conflicting calls. Expert knowledge, which considers structural analogs and mechanisms of activity, has been valuable when models return an indeterminate (equivocal) result or no prediction (out-of-domain). A retrospective analysis of 1002 impurities evaluated in drug regulatory applications between April 2017 and March 2019 assessed the impact of expert review on (Q)SAR predictions. Expert knowledge overturned the default predictions for 26% of the impurities and resolved 91% of equivocal predictions and 75% of out-of-domain calls. Of the 261 overturned default predictions, 15% were upgraded to equivocal or positive and 79% were downgraded to equivocal or negative. Chemical classes with the most overturns were primary aromatic amines (46%), aldehydes (45%), Michael-reactive acceptors (37%), and non-primary alkyl halides (33%). Additionally, low confidence predictions were the most often overturned. Collectively, the results suggest that expert knowledge continues to play an important role in an ICH M7 (Q)SAR prediction workflow and triaging predictions based on chemical class and probability can improve (Q)SAR review efficiency.

Iminopyrimidinones: a novel pharmacophore for the development of orally active renin inhibitors.

The development of renin inhibitors with favorable oral pharmacokinetic profiles has been a longstanding challenge for the pharmaceutical industry. As part of our work to identify inhibitors of BACE1, we have previously developed iminopyrimidinones as a novel pharmacophore for aspartyl protease inhibition. In this letter we describe how we modified substitution around this pharmacophore to develop a potent, selective and orally active renin inhibitor.

Lead optimization of a sulfonylurea-based piperazine pyridazinone series of glucan synthase inhibitors.

The structure-activity relationship studies of a novel sulfonylurea series of piperazine pyridazine-based small molecule glucan synthase inhibitors is described. The optimization of PK profiles within the series led to the discovery of several compounds with improved pharmacokinetic profiles which demonstrated in vitro potency against clinically relevant strains. However, the advancement of compounds from this series into a non-lethal systemic fungal infection model failed to show in vivo efficacy.

The optimization of pyridazinone series of glucan synthase inhibitors.

A detailed structure-activity relationship study of a novel series of pyridazine-based small molecule glucan synthase inhibitors is described. The optimization of the PK profile of this series led to the discovery of compound 11g, which demonstrated in vivo potency ip in a lethal fungal infection model.

SAR studies of pyridazinone derivatives as novel glucan synthase inhibitors.

A novel series of pyridazinone analogs has been developed as potent ß-1,3-glucan synthase inhibitors through structure-activity relationship study of the lead 5-[4-(benzylsulfonyl)piperazin-1-yl]-4-morpholino-2-phenyl-pyridazin-3(2H)-one (1). The effect of changes to the core structure is described in detail. Optimization of the sulfonamide moiety led to the identification of important compounds with much improved systematic exposure while retaining good antifungal activity against the fungal strains Candida glabrata and Candida albicans.