ABSTRACT
The synthesis and SAR of a novel class of spirobenzofuranpiperidinyl-derived alkanoic acids 6-34 as sphingosine S1P5 receptor agonists are described. The target compounds generally elicit high S1P5 receptor agonistic potencies and in general are selective against both S1P1 and S1P3 receptor subtypes. The key compound 32 shows a high bioavailability of 73% and a CNS/plasma ratio of 0.8 after oral administration in rats.
Subject(s)
Benzofurans/pharmacology , Receptors, Lysosphingolipid/agonists , Administration, Oral , Animals , Benzofurans/chemistry , Biological Availability , Dose-Response Relationship, Drug , Humans , Molecular Docking Simulation , Molecular Structure , Rats , Structure-Activity RelationshipABSTRACT
The Ullmann coupling has been used extensively as a synthetic tool for the formation of C-C bonds on surfaces. Thus far, most syntheses made use of aryl bromides or aryl iodides. We investigated the applicability of an aryl chloride in the bottom-up assembly of graphene nanoribbons. Specifically, the reactions of 10,10'-dichloro-9,9'-bianthryl (DCBA) on Au(111) were studied. Using atomic resolution non-contact AFM, the structure of various coupling products and intermediates were resolved, allowing us to reveal the important role of the geometry of the intermediate aryl radicals in the formation mechanism. For the aryl chloride, cyclodehydrogenation occurs before dehalogenation and polymerization. Due to their geometry, the planar bisanthene radicals display a different coupling behavior compared to the staggered bianthryl radicals formed when aryl bromides are used. This results in oligo- and polybisanthenes with predominantly fluoranthene-type connections.
ABSTRACT
Pd(OAc)(2)/3 is an efficient catalyst system for the base-free oxidative Heck reaction that outperforms the currently available catalysts for the more challenging substrates studied. The catalyst system is highly selective, and works at room temperature with dioxygen as the oxidant.
Subject(s)
Imines/chemistry , Organometallic Compounds/chemistry , Palladium/chemistry , Catalysis , Oxidation-Reduction , Substrate SpecificityABSTRACT
The syntheses of several 1-aryl-4-(arylpyridylmethyl)piperazines (4) and their affinities for dopamine D(2) and serotonin 5-HT(1A) receptors are described. The compounds were evaluated both in vitro and in vivo, resulting in the identification of the drug candidate SLV313 (4e) with equipotent and full D(2) receptor antagonism and 5-HT(1A) receptor agonism. Minor structural modifications in SLV313 revealed the possibility of designing compounds possessing varying degrees of partial agonism on one or both target receptors.
Subject(s)
Antipsychotic Agents/chemistry , Antipsychotic Agents/pharmacology , Dopamine D2 Receptor Antagonists , Piperazines/chemistry , Piperazines/pharmacology , Serotonin 5-HT1 Receptor Antagonists , Administration, Oral , Animals , Antipsychotic Agents/administration & dosage , Dogs , Drug Design , Drug Evaluation, Preclinical , Female , Injections, Intravenous , Ligands , Male , Molecular Structure , Piperazines/administration & dosage , Rats , Stereoisomerism , Structure-Activity RelationshipABSTRACT
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.
