ABSTRACT
A high-throughput screening (HTS) campaign identified a class of heteroaryl piperazines with excellent baseline affinity and selectivity for phosphoinositide 3-kinase δ (PI3Kδ) over closely related isoforms. Rapid evaluation and optimization of structure-activity relationships (SAR) for this class, leveraging the modular nature of this scaffold, facilitated development of this hit class into a series of potent and selective inhibitors of PI3Kδ. This effort culminated in the identification of 29, which displayed excellent potency in enzyme and cell-based assays, as well as favorable pharmacokinetic and off-target profiles.
Subject(s)
Class I Phosphatidylinositol 3-Kinases/antagonists & inhibitors , High-Throughput Screening Assays/methods , Piperazines/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Humans , Piperazines/pharmacology , Protein Kinase Inhibitors/pharmacology , Structure-Activity RelationshipABSTRACT
The parallel medicinal chemistry (PMC) was effectively applied to accelerate the optimization of diacylglycerol O-acyltransferase I (DGAT-1) inhibitors. Through a highly collaborative and iterative library design, synthesis and testing, a benzimidazole lead was rapidly and systematically advanced to a highly potent, selective and bioavailable DGAT1 inhibitor with the potential for further development.
Subject(s)
Benzimidazoles/pharmacology , Diacylglycerol O-Acyltransferase/antagonists & inhibitors , Drug Discovery , Enzyme Inhibitors/pharmacology , Benzimidazoles/chemical synthesis , Benzimidazoles/chemistry , Chemistry, Pharmaceutical , Diacylglycerol O-Acyltransferase/metabolism , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Molecular Structure , Structure-Activity RelationshipABSTRACT
A novel parallel medicinal chemistry (PMC)-enabled synthesis of 1H-pyrazolo[3,4-d]pyrimidines employing condensation of easily accessible N-pyrazolylamides and nitriles has been developed. The presented studies describe singleton and library enablements that allowed rapid generation of molecular diversity to examine C4 and C6 vectors. This chemistry enabled access to challenging alkyl substituents, expanding the overall chemical space beyond that available via typical C(sp2)-C(sp2) coupling and SNAr transformations. Furthermore, monomer group interconversions allowing the use of larger and more diverse amides and carboxylic acids as precursors to nitriles are discussed.
Subject(s)
Amides/chemistry , Nitriles/chemistry , Pyrazoles/chemistry , Pyrimidines/chemistry , Chemistry, Pharmaceutical , Drug Carriers , Humans , Particle Size , Pyrazoles/chemical synthesis , Pyrimidines/chemical synthesis , Surface PropertiesABSTRACT
The tubulysin class of natural products has attracted much attention from the medicinal chemistry community due to its potent cytotoxicity against a wide range of human cancer cell lines, including significant activity in multidrug-resistant carcinoma models. As a result of their potency, the tubulysins have become an important tool for use in targeted therapy, being widely pursued as payloads in the development of novel small molecule drug conjugates (SMDCs) and antibody-drug conjugates (ADCs). A structure-based and parallel medicinal chemistry approach was applied to the synthesis of novel tubulysin analogues. These efforts led to the discovery of a number of novel and potent cytotoxic tubulysin analogues, providing a framework for our simultaneous report, which highlights the discovery of tubulysin-based ADCs, including use of site-specific conjugation to address in vivo stability of the C-11 acetate functionality.