ABSTRACT
CRTh2 (DP(2)) is a prostaglandin D(2) receptor implicated in the recruitment of eosinophils and basophils within the asthmatic lung. Here we report the discovery of a novel series of 3-indolyl sultam antagonists with low nM affinity for CRTh2. These compounds proved to be selective over the other primary prostaglandin D(2) receptor (DP1) as well as the thromboxane A(2) receptor (TP).
Subject(s)
Indoles/chemistry , Indoles/pharmacology , Receptors, Immunologic/antagonists & inhibitors , Receptors, Prostaglandin/antagonists & inhibitors , Sulfonamides/pharmacology , Esterification , Humans , Sulfonamides/chemistryABSTRACT
5-HT2C agonists have shown efficacy in limiting food consumption and thus may serve as an important drug class in combating obesity. We describe the design and synthesis of a novel tricyclic single-nitrogen scaffold that was used to produce 5-HT2C agonists. SAR was developed around this chemotype and compounds were identified that were potent (Ki<15 nM) and selective relative to other 5-HT2 receptors. The most promising compound displayed a good pharmacokinetic profile in multiple animal species, and was efficacious in an acute feeding study in rats.
Subject(s)
Nitrogen/chemistry , Serotonin 5-HT2 Receptor Agonists , Serotonin Receptor Agonists/chemical synthesis , Serotonin Receptor Agonists/pharmacology , Animals , Dogs , Drug Design , Feeding Behavior/drug effects , Half-Life , Rats , Serotonin Receptor Agonists/chemistry , Serotonin Receptor Agonists/pharmacokinetics , Structure-Activity RelationshipABSTRACT
The 5-HT2C receptor has been implicated in the regulation of appetite. As such, small molecule agonists to this receptor may serve as novel therapies to combat obesity. We describe here the identification, synthesis, and SAR of a 5-HT2C agonist from a unique pyrimidine-diazabicyclo[3.3.0]octane series. This compound displayed good potency at the 5-HT2C receptor, modest selectivity relative to other 5-HT2 receptors, and was efficacious in an acute feeding study in rats.
Subject(s)
Aza Compounds/chemistry , Aza Compounds/pharmacology , Bridged Bicyclo Compounds/chemistry , Bridged Bicyclo Compounds/pharmacology , Pyrimidines/chemistry , Pyrimidines/pharmacology , Receptor, Serotonin, 5-HT2C/metabolism , Serotonin 5-HT2 Receptor Agonists , Amines/chemistry , Animals , Aza Compounds/chemical synthesis , Bridged Bicyclo Compounds/chemical synthesis , Molecular Structure , Pyrimidines/chemical synthesis , Rats , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The chemoattractant receptor-homologous molecule expressed on T(H)2 cells (CRTH-2), also found on eosinophils and basophils, is a prostaglandin D2 receptor involved in the recruitment of these cell types during an inflammatory response. In this report, we describe the synthesis and optimization of a ramatroban isostere that is a selective and potent antagonist of CRTH-2 which may be useful in the treatment of certain diseases.
Subject(s)
Carbazoles/chemistry , Carbazoles/pharmacology , Receptors, Immunologic/antagonists & inhibitors , Receptors, Prostaglandin/antagonists & inhibitors , Sulfonamides/chemistry , Sulfonamides/pharmacology , Anti-Asthmatic Agents/chemistry , Anti-Asthmatic Agents/pharmacology , Isomerism , Models, Chemical , Molecular Conformation , Molecular Structure , Structure-Activity RelationshipABSTRACT
The dopamine D(3) receptor subtype has been targeted as a potential neurochemical modulator of the behavioral actions of psychomotor stimulants, such as cocaine. Previous synthetic studies provided structural requirements for high affinity binding to D(3) receptors which included a 2,3-dichloro-phenylpiperazine linked to an arylamido function via a butyl chain. To reduce lipophilicity of these agents and further investigate optimal conformation, a second series of 15 novel ligands was designed that included heteroaromatic substitution and unsaturated alkyl linkers. These compounds were synthesized and evaluated for binding at rat D(3) and D(2) receptors stably expressed in Sf9 cells. D(3) binding affinities ranged from K(i)=0.6-1080 nM, with a broad range of D(3)/D(2) selectivities (2-97). The discovery of potent, selective and bioavailable D(3) receptor ligands will provide essential molecular probes to elucidate the role D(3) receptors play in the psychomotor stimulant and reinforcing effects of cocaine.
