10.1016/j.bmcl.2010.01.063
The research focuses on the development of decahydroisoquinoline derivatives as novel non-peptidic, potent, and subtype-selective somatostatin SST3 receptor antagonists. The study began with non-peptidic SST1-selective somatostatin receptor antagonists and through directed structural modifications, identified compounds with mixed SST1/SST3 affinity. Systematic optimization of these initial leads resulted in the discovery of enantiomerically pure, highly potent, and SST3-subtype selective somatostatin antagonists based on a (4S,4aS,8aR)-decahydroisoquinoline-4-carboxylic acid core moiety. The experiments involved the synthesis of various compounds through a series of chemical reactions, including reductive amination, Boc protection, ester hydrolysis, amide formation, and amine deprotection. The synthesized compounds were then evaluated for their binding affinities to human recombinant SST3 and SST1 receptors, as well as their selectivity over other receptor subtypes. The analyses included radioligand binding assays, cAMP-based functional assays, pharmacokinetic studies in rodents, and assessments for genotoxicity and cytochrome P450 inhibition. The research led to the identification of ACQ090 as a promising candidate with high SST3 receptor affinity, good selectivity, and favorable pharmacokinetic properties.
10.1021/ol015988w
The study investigates the use of vinyl imidates in intramolecular Diels?Alder reactions to efficiently synthesize cis-fused perhydroisoquinoline ring systems, exemplified by the preparation of an intermediate, isoquinoline 2, which can be transformed into reserpine. The researchers employed N-acylvinylimidates as the 2π electron component in these reactions, leveraging their potential for stereochemical control. The process began with the Stille coupling of vinylstannane 66 and methyl (3E)-bromopropenoate (7) to produce diene 8, which was then converted to diene 5 via kinetic deconjugation and saponification. The Diels-Alder precursor was formed by coupling diene 5 with 1-aza-2-ethoxy-1,3-butadiene (9), mediated by 2-chloro-1-methylpyridinium iodide, yielding N-acylvinylimidate 4. Cycloaddition of this compound resulted in the formation of cycloadducts, with the major product, 3, having a cis-ring fusion. Further steps included reduction, carbamate formation, hydroboration, oxidation, and acetylation to complete the synthesis of perhydroisoquinoline 2. This work highlights the utility of vinyl imidates in constructing complex isoquinoline ring systems with significant stereochemical complexity.
Xi
