Discovery of a Thiadiazole-Pyridazine-Based Allosteric Glutaminase 1 Inhibitor Series That Demonstrates Oral Bioavailability and Activity in Tumor Xenograft Models.

Tumors have evolved a variety of methods to reprogram conventional metabolic pathways to favor their own nutritional needs, including glutaminolysis, the first step of which is the hydrolysis of glutamine to glutamate by the amidohydrolase glutaminase 1 (GLS1). A GLS1 inhibitor could potentially target certain cancers by blocking the tumor cell's ability to produce glutamine-derived nutrients. Starting from the known GLS1 inhibitor bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide, we describe the medicinal chemistry evolution of a series from lipophilic inhibitors with suboptimal physicochemical and pharmacokinetic properties to cell potent examples with reduced molecular weight and lipophilicity, leading to compounds with greatly improved oral exposure that demonstrate in vivo target engagement accompanied by activity in relevant disease models.

Synthesis of functionalized cyanopyrazoles via magnesium bases.

4-Alkyl- and 4-H-pyrazoles were sequentially metalated using TMPMgCl·LiCl, and their reaction with electrophiles afforded 3-aryl-4-alkyl-5-cyanopyrazoles.

2-(Aryl-sulfonyl)oxetanes as designer 3-dimensional fragments for fragment screening: synthesis and strategies for functionalisation.

2-Sulfonyl-oxetanes have been prepared, affording non-planar structures with desirable physicochemical properties for fragment based drug discovery. The oxetane motif was formed by an intramolecular C-C bond formation. The fragments were further functionalised via organometallic intermediates at the intact oxetane and aromatic rings.

Neutral 5-substituted 4-anilinoquinazolines as potent, orally active inhibitors of erbB2 receptor tyrosine kinase.

Neutral 5-substituted 4-anilinoquinazolines addressed high in vivo clearance and phospholipidosis associated with previous basic compounds. A representative compound 8a inhibited tumor growth in a mouse xenograft model when co-administered with the cytochrome P450 inhibitor 1-aminobenzotriazole (ABT), and data are consistent with pharmacology primarily reflecting inhibition of erbB2 receptor tyrosine kinase.