ABSTRACT
Spiroindoline urea derivatives, designed to act as NPY Y5 receptor antagonists, were synthesized and their structure-activity relationships were investigated. Of these derivatives, compound 3a showed good Y5 binding affinity with favorable pharmacokinetic properties. Compound 3a significantly inhibited bPP Y5 agonist-induced food intake in rats, and suppressed body weight gain in DIO mice.
Subject(s)
Anti-Obesity Agents/chemistry , Anti-Obesity Agents/pharmacology , Indoles/chemistry , Indoles/pharmacology , Receptors, Neuropeptide Y/antagonists & inhibitors , Receptors, Neuropeptide Y/metabolism , Animals , Anti-Obesity Agents/chemical synthesis , Anti-Obesity Agents/pharmacokinetics , Biological Availability , Body Weight/drug effects , Eating/drug effects , Indoles/chemical synthesis , Indoles/pharmacokinetics , Mice , Mice, Inbred C57BL , Molecular Structure , Protein Binding , Rats , Rats, Sprague-Dawley , Receptors, Neuropeptide Y/agonists , Spiro Compounds/chemical synthesis , Spiro Compounds/chemistry , Spiro Compounds/pharmacokinetics , Spiro Compounds/pharmacology , Structure-Activity RelationshipABSTRACT
Continuing medicinal chemistry studies to identify spiropiperidine-derived NPY Y5 receptor antagonists are described. Aryl urea derivatives of a variety of spiropiperidines were tested for their NPY Y5 receptor binding affinities. Of the spiropiperidines so far examined, spiro[3-oxoisobenzofurane-1(3H),4'-piperidine] was a useful scaffold for producing orally active NPY Y5 receptor antagonists. Oral administration of 5c significantly inhibited the Y5 agonist-induced food intake in rats with a minimum effective dose of 3mg/kg. In addition, this compound was efficacious in decreasing body weight in diet-induced obese mice.
Subject(s)
Anti-Obesity Agents/chemistry , Piperidines/chemistry , Receptors, Neuropeptide Y/antagonists & inhibitors , Spiro Compounds/chemistry , Urea/analogs & derivatives , Administration, Oral , Animals , Anti-Obesity Agents/chemical synthesis , Anti-Obesity Agents/pharmacology , Eating , Humans , Mice , Piperidines/chemical synthesis , Piperidines/pharmacology , Rats , Receptors, Neuropeptide Y/metabolism , Spiro Compounds/chemical synthesis , Spiro Compounds/pharmacology , Urea/chemical synthesis , Urea/pharmacology , Weight LossABSTRACT
A series of novel imidazoline derivatives was synthesized and evaluated as neuropeptide Y (NPY) Y5 receptor antagonists. Optimization of previously reported imidazoline leads, 1a and 1b, was attempted by introduction of substituents at the 5-position on the imidazoline ring and modification of the bis(4-fluorphenyl) moiety. A number of potent derivatives without human ether-a-go-go related gene potassium channel (hERG) activity were identified. Selected compounds, including 2a, were shown to have excellent brain and CSF permeability. Compound 2a displayed a suitable pharmacokinetic profile for chronic in vivo studies and potently inhibited D-Trp(34)NPY-induced acute food intake in rats. Oral administration of 2a resulted in a potent reduction of body weight in a diet-induced obese mouse model.
Subject(s)
Anti-Obesity Agents/chemistry , Ether-A-Go-Go Potassium Channels/metabolism , Imidazolines/pharmacology , Obesity/drug therapy , Receptors, Neuropeptide Y/antagonists & inhibitors , Animals , Anti-Obesity Agents/chemical synthesis , Anti-Obesity Agents/pharmacology , Brain/metabolism , Cerebrospinal Fluid/metabolism , Disease Models, Animal , Drug Discovery , ERG1 Potassium Channel , Humans , Imidazolines/chemical synthesis , Imidazolines/chemistry , Pharmacokinetics , Protein Binding/drug effects , Rats , Structure-Activity Relationship , Weight Loss/drug effectsABSTRACT
(9S)-9-(2-Hydroxy-4,4-dimethyl-6-oxo-1-cyclohexen-1-yl)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-xanthen-1-one ((S)-1) was identified as a selective and orally active neuropeptide Y Y5 receptor antagonist. The structure-activity relationship for this structural class was investigated and showed that limited substitution on the phenyl ring was tolerated and that modification of the 4,4-dimethyl group of the cyclohexenone and the 3,3-dimethyl group of the xanthenone parts slightly improved potency. The plasma concentration-time profile after oral administration of (S)-1 in Sprague-Dawley (SD) rats showed significant in vivo racemization of (S)-1 and that (S)-1 is cleared much more quickly than (R)-1. The duration of (S)-1 in SD rats after oral administration of (RS)-1 racemate was twice as long as that following oral administration of (S)-1. The C max values of (S)-1 after administration of (S)-1 and (RS)-1 were comparable, and the brain to plasma ratio for (S)-1 was 0.34 in SD rats. In our acute D-Trp (34)NPY-induced food intake model, both (S)-1 and (RS)-1 showed potent and dose-dependent efficacy. Therefore, the use of (RS)-1 is suitable for studies that require sustained plasma exposure of (S)-1.
Subject(s)
Cyclohexanones/administration & dosage , Cyclohexanones/chemistry , Receptors, Neuropeptide Y/antagonists & inhibitors , Receptors, Neuropeptide Y/metabolism , Xanthenes/administration & dosage , Xanthenes/chemistry , Administration, Oral , Animal Feed , Animals , Blood-Brain Barrier/metabolism , Cell Line , Cyclohexanones/chemical synthesis , Cyclohexanones/metabolism , Humans , Molecular Structure , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Xanthenes/chemical synthesis , Xanthenes/metabolismABSTRACT
A series of phenylpiperazine derivatives were synthesized and evaluated for their neuropeptide Y (NPY) Y5 receptor antagonistic activities. The benzindane portion of 2 was replaced by 1-phenylpiperazine, resulting in novel urea derivative 3f. Subsequent optimization of the phenylpiperazine template by substitution of the phenyl moiety resulted in a series of (2-methanesulfonamidephenyl)piperazine derivatives that showed potent binding affinity and antagonistic activity for the Y5 receptor.
Subject(s)
Piperazines/chemistry , Receptors, Neuropeptide Y/antagonists & inhibitors , Humans , Molecular Structure , Piperazines/chemical synthesis , Receptors, Neuropeptide Y/metabolism , Structure-Activity RelationshipABSTRACT
Novel arylpyrazole derivatives were synthesized and evaluated as neuropeptide Y (NPY) Y5 receptor antagonists. Compound (-)-7, which features a novel chiral 2,3-dihydro-1H-cyclopenta[a]naphthalene moiety, showed good binding affinity and antagonistic activity for the Y5 receptor. After intracerebroventricular administration in SD rats, (-)-7 significantly inhibited food intake that was induced by the centrally administered Y5-preferring agonist, bovine pancreatic polypeptide, but had only a negligible effect on NPY-induced feeding.
