The total synthesis of (±)-goniomitine has been accomplished in 17 linear steps with 5.2% overall yield starting from commercially available
δ-valerolactam. A synthetic highlight includes the first application of a formal [3 + 2] cycloaddition between a highly functionalized nitrile and
a donor−acceptor cyclopropane to prepare an indole nucleus. The use of a microwave reactor is shown to greatly improve the reaction times
for two steps.
The formal [3+2] dipolar cycloaddition (or annulation) of donor‐acceptor cyclopropanoate esters with pyridines and 5‐nitroquinoline is reported. Electron‐deficient pyridine dipolarophiles (R=CN, CO2Et, COMe) participate in the annulation whereas electron rich species do not. The product 2,3‐dihydroindolizines undergo rapid autooxidation, and the X‐ray structures for two of the aromatic products are reported.
Agonism of the 5-HT receptor represents one of the most well-studied and clinically proven mechanisms for pharmacological weight reduction. Selectivity over the closely related 5-HT and 5-HT receptors is critical as their activation has been shown to lead to undesirable side effects and major safety concerns. In this communication, we report the development of a new screening paradigm that utilizes an active site mutant D134A (D3.32) 5-HT receptor to identify atypical agonist structures. We additionally report the discovery and optimization of a novel class of nonbasic heterocyclic amide agonists of 5-HT. SAR investigations around the screening hits provided a diverse set of potent agonists at 5-HT with high selectivity over the related 5-HT and 5-HT receptor subtypes. Further optimization through replacement of the amide with a variety of five- and six-membered heterocycles led to the identification of 6-(1-ethyl-3-(quinolin-8-yl)-1H-pyrazol-5-yl)pyridazin-3-amine (69). Oral administration of 69 to rats reduced food intake in an ad libitum feeding model, which could be completely reversed by a selective 5-HT antagonist.
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