Andrew J. Zych

SAR studies of pyridazinone derivatives as novel glucan synthase inhibitors

A novel series of pyridazinone analogs has been developed as potent β-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.

Application of Polymer‐Supported Triphenylphosphine and Microwave Irradiation to the Palladium‐Catalyzed Cyanation of Aryl Triflates

Abstract A variety of aryl nitriles were prepared in excellent yield from the palladium(II) acetate–catalyzed cross‐coupling of aryl triflates and zinc cyanide under microwave irradiation conditions. To facilitate purification, polymer‐supported triphenylphosphine was used as the palladium ligand. Comparison to the corresponding thermal conditions revealed much shorter reaction times with comparable yields.

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.