A new series of lactam-derived EZH2 inhibitors was designed via ligand-based and physicochemical-property-based strategies to address metabolic stability and thermodynamic solubility issues associated with previous lead compound 1. The new inhibitors incorporated an sp hybridized carbon atom at the 7-position of the lactam moiety present in lead compound 1 as a replacement for a dimethylisoxazole group. This transformation enabled optimization of the physicochemical properties and potency compared to compound 1. Analysis of relationships between calculated log D (clogD) values and in vitro metabolic stability and permeability parameters identified a clogD range that afforded an increased probability of achieving favorable ADME data in a single molecule. Compound 23a exhibited the best overlap of potency and pharmaceutical properties as well as robust tumor growth inhibition in vivo and was therefore advanced as a development candidate (PF-06821497). A crystal structure of 23a in complex with the three-protein PRC2 complex enabled understanding of the key structural features required for optimal binding.

2-Aminopyridine-3,5-dicarbonitrile compounds were previously identified as mimetics of dominant-negative prion protein mutants and inhibit prion replication in cultured cells. Here, we report findings from a comprehensive structure-activity relationship study of the 6-aminopyridine-3,5-dicarbonitrile scaffold. We identify compounds with significantly improved bioactivity (approximately 40-fold) against replication of the infectious prion isoform (PrPSc) and suitable pharmacokinetic profiles to warrant evaluation in animal models of prion disease.

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A parallel synthetic strategy to the 9-aminoacridine scaffold of the classical anti-malarial drug quinacrine (2) is presented. The method features a new route to 9-chloroacridines that utilizes triflates of salicylic acid derivatives, which are commercially available in a variety of substitution patterns. The route allows ready variation of the two diversity elements present in this class of molecules: the tricyclic aromatic heterocyclic core, and the disubstituted diamine sidechain. In this study, a library of 175 compounds was designed, although only 93 of the final products had purities acceptable for screening. Impurity was generally due to incomplete removal of 9-acridones (18), a degradation product of the 9-chloroacridine synthetic intermediates. The library was screened against two strains of Plasmodium falciparum, including a model of the drug-resistant parasite, and six novel compounds were found to have IC 50 values in the low nanomolar range.

The substitution effects in the B-ring of 4-hydroxyquinoline on antimalarial activity against drug-resistant parasite strains are investigated. The key steps in the synthesis of libraries (VIII) and (X) consist of and addition-elimination reaction to afford the ene-amine precursor (IV) and the subsequent microwave-assisted cyclization step. Compounds with the shorter side chain, cf. (VIII), are consistently more potent, especially against the drug-resistant W2 strain. The most active compounds possess substituents at either the 6-or 7-position on the quinoline ring. In general, small electron-withdrawing groups yield active substitutions. -(MADRID, P. B.; SHERRILL, J.; LIOU, A. P.; WEISMAN, J. L.; DERISI, J. L.; GUY*, R. K.; Bioorg. Med. Chem. Lett. 15 (2005) 4, 1015-1018; Dep. Pharm. Chem., Sch. Pharm., Univ. Calif., San Francisco, CA 94143, USA; Eng.) -H. Hoennerscheid 25-144