ABSTRACT
The design of a new clinical candidate histamine-H(3) receptor antagonist for the potential treatment of excessive daytime sleepiness (EDS) is described. Phenethyl-R-2-methylpyrrolidine containing biphenylsulfonamide compounds were modified by replacement of the sulfonamide linkage with a sulfone. One compound from this series, 2j (APD916) increased wakefulness in rodents as measured by polysomnography with a duration of effect consistent with its pharmacokinetic properties. The identification of a suitable salt form of 2j allowed it to be selected for further development.
Subject(s)
Biphenyl Compounds/chemistry , Biphenyl Compounds/pharmacology , Histamine Antagonists/chemistry , Pyrrolidines/chemistry , Pyrrolidines/pharmacology , Receptors, Histamine H3/chemistry , Sulfones/chemistry , Animals , Area Under Curve , Brain/metabolism , Central Nervous System/drug effects , Chemistry, Pharmaceutical/methods , Drug Design , ERG1 Potassium Channel , Ether-A-Go-Go Potassium Channels/chemistry , Histamine Antagonists/pharmacokinetics , Humans , Inhibitory Concentration 50 , Mice , Models, Chemical , Pyrrolidines/antagonists & inhibitors , Rats , Sleep/drug effects , Temperature , Wakefulness/drug effectsABSTRACT
Antagonism of the histamine-H(3) receptor is one tactic being explored to increase wakefulness for the treatment of disorders such as excessive daytime sleepiness (EDS) as well as other sleep or cognitive disorders. Phenethyl-R-2-methylpyrrolidine containing biphenylsulfonamide compounds were shown to be potent and selective antagonists of the H(3) receptor. Several of these compounds demonstrated in vivo activity in a rat model of (R)-alpha-methyl histamine (RAMH) induced dipsogenia, and one compound (4e) provided an increase in wakefulness in rats as measured by polysomnographic methods. However, more detailed analysis of the PK/PD relationship suggested the presence of a common active metabolite which may preclude this series of compounds from further development.
Subject(s)
Biphenyl Compounds/chemistry , Drug Design , Drug Inverse Agonism , Histamine Antagonists/chemistry , Histamine Antagonists/pharmacology , Receptors, Histamine H3/metabolism , Sulfonamides/chemistry , Sulfonamides/pharmacology , Administration, Oral , Animals , Histamine Antagonists/administration & dosage , Histamine Antagonists/pharmacokinetics , Humans , Male , Rats , Rats, Sprague-Dawley , Sulfonamides/administration & dosage , Sulfonamides/pharmacokinetics , Thirst/drug effects , Wakefulness/drug effectsABSTRACT
The synthesis and SAR of a novel 3-benzazepine series of 5-HT2C agonists is described. Compound 7d (lorcaserin, APD356) was identified as one of the more potent and selective compounds in vitro (pEC50 values in functional assays measuring [(3)H]phosphoinositol turnover: 5-HT2C = 8.1; 5-HT2A = 6.8; 5-HT2B = 6.1) and was potent in an acute in vivo rat food intake model upon oral administration (ED50 at 6 h = 18 mg/kg). Lorcaserin was further characterized in a single-dose pharmacokinetic study in rat (t1/2 = 3.7 h; F = 86%) and a 28-day model of weight gain in growing Sprague-Dawley rat (8.5% decrease in weight gain observed at 36 mg/kg b.i.d.). Lorcaserin was selected for further evaluation in clinical trials for the treatment of obesity.
Subject(s)
Anti-Obesity Agents/chemical synthesis , Benzazepines/chemical synthesis , Obesity/drug therapy , Serotonin 5-HT2 Receptor Agonists , Animals , Anti-Obesity Agents/pharmacokinetics , Anti-Obesity Agents/pharmacology , Benzazepines/pharmacokinetics , Benzazepines/pharmacology , Cell Line , Eating/drug effects , Humans , Inositol 1,4,5-Trisphosphate/metabolism , Male , Rats , Rats, Sprague-Dawley , Stereoisomerism , Structure-Activity Relationship , Weight Gain/drug effectsABSTRACT
We report on the synthesis, biological evaluation and structure-activity relationships for a series of 3-benzazepine derivatives as 5-HT(2C) receptor agonists. The compounds were evaluated in functional assays measuring [3H] phosphoinositol turnover in HEK-293 cells transiently transfected with h5-HT(2C), h5-HT(2A) or h5-HT(2B) receptors. Several compounds are shown to be potent and selective 5-HT(2C) receptor agonists, which decrease food intake in a rat feeding model.
