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
A series of pyrimidine analogues derived from ATC0175 were potent antagonists of human MCH-R1 in vitro. Significantly improved receptor selectivity was achieved with several analogues from this series, but no improvement in brain partitioning was noted. One example from this series was shown to inhibit food intake and decrease body weight in a chronic study. However no clear correlation between the pharmacodynamic effect and the pharmacokinetic data with respect to brain concentration was discernible leading us to conclude that the observed effect was most likely not due to interaction with the MCH-R1.
Subject(s)
Anti-Obesity Agents/chemistry , Cyclohexylamines/chemistry , Pyrimidines/chemistry , Quinazolines/chemistry , Receptors, Somatostatin/antagonists & inhibitors , Administration, Oral , Animals , Anti-Obesity Agents/chemical synthesis , Anti-Obesity Agents/pharmacokinetics , Eating , Humans , Male , Pyrimidines/chemical synthesis , Pyrimidines/pharmacokinetics , Rats , Rats, Sprague-Dawley , Receptors, Somatostatin/metabolism , Structure-Activity Relationship , Weight LossABSTRACT
Recent developments in sleep research suggest that antagonism of the serotonin 5-HT(2A) receptor may improve sleep maintenance insomnia. We herein report the discovery of a series of potent and selective serotonin 5-HT(2A) receptor antagonists based on a phenethylpiperazine amide core structure. When tested in a rat sleep pharmacology model, these compounds increased both sleep consolidation and deep sleep. Within this series of compounds, an improvement in the metabolic stability of early leads was achieved by introducing a carbonyl group into the phenethylpiperazine linker. Of note, compounds 14 and 27 exhibited potent 5-HT(2A) receptor binding affinity, high selectivity over the 5-HT(2C) receptor, favorable CNS partitioning, and good pharmacokinetic and early safety profiles. In vivo, these two compounds showed dose-dependent, statistically significant improvements on deep sleep (delta power) and sleep consolidation at doses as low as 0.1 mg/kg.
Subject(s)
Amides/chemical synthesis , Piperazines/chemical synthesis , Pyrazoles/chemical synthesis , Serotonin 5-HT2 Receptor Antagonists , Sleep Initiation and Maintenance Disorders/drug therapy , Sleep/drug effects , Administration, Oral , Amides/pharmacokinetics , Amides/pharmacology , Animals , Biological Availability , Blood Proteins/metabolism , Brain/metabolism , Dogs , Drug Inverse Agonism , Haplorhini , Humans , Male , Microsomes, Liver/metabolism , Piperazines/pharmacokinetics , Piperazines/pharmacology , Protein Binding , Pyrazoles/pharmacokinetics , Pyrazoles/pharmacology , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
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
GPR119 is a rhodopsin-like GPCR expressed in pancreatic beta-cells and incretin releasing cells in the GI tract. As with incretins, GPR119 increases cAMP levels in these cell types, thus making it a highly attractive potential target for the treatment of diabetes. The discovery of the first reported potent agonist of GPR119, 2-fluoro-4-methanesulfonyl-phenyl)-{6-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-amine (8g, AR231453), is described starting from an initial inverse agonist screening hit. Compound 8g showed in vivo activity in rodents and was active in an oral glucose tolerance test in mice following oral administration.