Two distinct classes of novel pyrazolinecarboxamides as potent cannabinoid CB1 receptor agonists.

The synthesis and SAR of 3-alkyl-4-aryl-4,5-dihydropyrazole-1-carboxamides 1-23 and 1-alkyl-5-aryl-4,5-dihydropyrazole-3-carboxamides 24-27 as two novel cannabinoid CB(1) receptor agonist classes were described. The target compounds elicited high affinities to the CB(1) as well as the CB(2) receptor and were found to act as CB(1) receptor agonists. The key compound 19 elicited potent CB(1) agonistic and CB(2) inverse agonistic properties in vitro and showed in vivo activity in a rodent model for multiple sclerosis after oral administration.

Synthesis and SAR of novel imidazoles as potent and selective cannabinoid CB2 receptor antagonists with high binding efficiencies.

The synthesis and structure-activity relationship studies of imidazoles are described. The target compounds 6-20 represent a novel chemotype of potent and CB(2)/CB(1) selective cannabinoid CB(2) receptor antagonists/inverse agonists with very high binding efficiencies in combination with favourable logP and calculated polar surface area values. Compound 12 exhibited the highest CB(2) receptor affinity (K(i)=1.03 nM) in this series, as well as the highest CB(2)/CB(1) subtype selectivity (>9708-fold).

Novel indole and azaindole (pyrrolopyridine) cannabinoid (CB) receptor agonists: design, synthesis, structure-activity relationships, physicochemical properties and biological activity.

The discovery, synthesis and structure-activity relationship (SAR) of a novel series of cannabinoid 1 (CB(1)) and cannabinoid 2 (CB(2)) receptor ligands are reported. Based on the aminoalkylindole class of cannabinoid receptor agonists, a biphenyl moiety was introduced as novel lipophilic indole 3-acyl substituent in 11-16. Furthermore, the 3-carbonyl tether was replaced with a carboxamide linker in 17-20 and the azaindole (pyrrolopyridine) nucleus was designed as indole bioisostere with improved physicochemical properties in 21-25. Through these SAR efforts, several high affinity CB(1)/CB(2) dual cannabinoid receptor ligands were identified. Indole-3-carboxamide 17 displayed single-digit nanomolar affinity and ~80 fold selectivity for CB(1) over the CB(2) receptor. The azaindoles displayed substantially improved physicochemical properties (lipophilicity; aqueous solubility). Azaindole 21 elicited potent cannabinoid activity. Cannabinoid receptor agonists 17 and 21 potently modulated excitatory synaptic transmission in an acute rat brain slice model of cannabinoid receptor-modulated neurotransmission.

Piperazinyl oxime ethers as NK-1 receptor antagonists.

The synthesis and structure-activity relations for a new class of centrally active NK-1 receptor antagonists are described. The new compounds are based on piperazine 2 and contain an oxime ether functionality. Several new compounds have high affinity for the NK-1 receptor and show good antagonistic activity in the gerbil foot-tapping assay.