The scope of the acid-mediated 3-component synthesis of thiadiazines was investigated. A selective functionalization of the six-membered heterocyclic core structure was accomplished by sequential alkylations, saponifications, and coupling reactions. Several new analogs of a dihydropyrimidinone Hsp70 chaperone agonist, MAL1-271, showed promising activity in a cell based model of Huntington’s disease.

2503 Background: Imatinib mesylate, a potent inhibitor of Bcr-Abl and c-kit tyrosine kinases, is widely used to treat gastrointestinal stromal tumors and Philadelphia chromosome-positive leukemias. Imatinib often causes gastric upset and is therefore frequently administered with a proton pump inhibitor (PPI). Yet, the resulting elevated gastric pH, delayed gastric emptying, and inhibition of ABC transporters in the gut could change imatinib absorption, thereby affecting the therapeutic effectiveness of imatinib. To test this hypothesis, we sought to define the effect of PPI on the plasma pharmacokinetics of imatinib. Methods: 11 healthy subjects (6 M, 5 F; 21–56 years) were enrolled in a 2-period, open-label, randomized cross-over, fixed- sequence study. In one period, they received a single 400 mg dose of imatinib p.o., in the other, 40 mg omeprazol daily for five days followed by a single 400 mg dose of imatinib p.o.. The periods were separated by a wash-out period of ≥ 14 days. Plasma samples from 0–72 h after dosing were obtained. Plasma concentrations of imatinib and its active metabolite CGP74588 were determined with an LC-MS assay and data were analyzed non-compartmentally. The study was powered to detect a 30% difference in imatinib AUC with 80% power and a 5% type I error. Results: See Table . Conclusions: This study demonstrates that the use of PPI to treat imatinib-induced gastric upset does not significantly affect imatinib plasma AUC. Support: Novartis; NIH/NCRR/CTSA Grant UL1 RR024153 [Table: see text] [Table: see text]

SummaryHydrozirconation of 1-hexyne, the addition to in situ prepared N-acyliminium species, and ring-closing metathesis (RCM) were key steps in the preparation of a tricyclic isoindolinone scaffold. An unusual alkene isomerization process during the RCM was identified and studied in some detail. Chemical diversification for library synthesis was achieved by a subsequent alkene epoxidation and zinc-mediated aminolysis reaction. The resulting library products provided selective hits among a large number of high-throughput screens reported in PubChem, thus illustrating the utility of the novel scaffold.