Spiro-1-benzofuranpiperidinylalkanoic acids as a novel and selective sphingosine S1P receptor agonist chemotype.

The synthesis and SAR of a novel class of spirobenzofuranpiperidinyl-derived alkanoic acids 6-34 as sphingosine S1P receptor agonists are described. The target compounds generally elicit high S1P receptor agonistic potencies and in general are selective against both S1P and S1P receptor subtypes. The key compound 32 shows a high bioavailability of 73% and a CNS/plasma ratio of 0.

7-Azaindole derivatives as potential partial nicotinic agonists.

We have investigated a series of 7-azaindoles as potential partial agonists of the alpha4beta2 nicotinic acetylcholine receptor (nAChR). Three series of 7-azaindole derivatives have been synthesized and evaluated for rat brain neuronal nicotinic receptor affinity and functional activity. Compound (+)-51 exhibited the most potent nAChR binding (Ki = 10 nM).

Design, synthesis and biological activity of rigid cannabinoid CB1 receptor antagonists.

The design, synthesis and biological activities of potent pyrazole-based tricyclic CB1 receptor antagonists (2) are described. The key synthetic step involves the ring closure of the lithiated alpha, gamma-keto ester adduct (4). The optimal nitroderivative (28) in this series exhibits a high CB1 receptor affinity (pKi=7.