The PI3K/AKT/mTOR pathway is among the most frequently altered pathways in cancer cell growth and survival.

The design and synthesis of a series of 11,12-cyclic carbamate derivatives of 6-O-methylerythromycin A that are novel, nonpeptide LHRH antagonists, is described. The macrolide antagonist 1, discovered during a screen of our chemical repository, was compared to a macrocyclic peptide antagonist 2 using molecular modeling, thus providing a model for the design of more potent antagonists. Medicinal chemistry efforts to find a replacement for cladinose at position 3 of the erythronolide core provided a series of oxazolidinone carbamates that were equally as active as the cladinose-containing parent macrolides. The descladinose LHRH antagonist 14 has 1-2 nM affinity for both rat and human LHRH receptors and is a potent inhibitor of LH release (pA2 = 8.76) in vitro. In vivo, 14 was found to produce a dose-dependent suppression of LH in male castrate rats via both i.v. and p.o. dosing.

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A series of substituted 2‐aryl imidazo[1,2‐a]pyridines has been prepared in which a variety of substituents are introduced on the 4′‐position of the phenyl ring and on the 3, 5, 6 or 7 position of the heterocyclic ring. Most examples have acetamido, bromo, cyano, or formyl substituents at the 4′‐position. Analogous imidazo‐[2,1‐b]fhiazoles and imidazo[1,2‐a]pyrimidines have also been prepared. Another series of compounds consisting of 4′‐formylphenoxymethyl derivatives of imidazole, the three positional isomers of pyridine, thiazole, benzimidazole and ring‐substituted imidazo[1,2‐a]pyridines has been prepared. 2‐(4′‐Formylphenylethenyl) derivatives of imidazole and imidazo[1,2‐a]pyridine were also prepared.

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