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
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
Novel imidazoline derivatives were discovered to be potent neuropeptide Y Y5 receptor antagonists. High-throughput screening of Merck sample collections against the human Y5 receptor resulted in the identification of 2,4,4-triphenylimidazoline (1), which had an IC(50) of 54nM. Subsequent optimization led to the identification of several potent derivatives.
Subject(s)
Chemistry, Pharmaceutical/methods , Imidazoles/chemistry , Receptors, Neuropeptide Y/chemistry , Animals , Brain/metabolism , Carboxylic Acids/chemistry , Cerebrospinal Fluid/metabolism , Drug Design , Humans , Inhibitory Concentration 50 , Mice , Models, Chemical , Molecular Structure , Structure-Activity RelationshipABSTRACT
Reaction of 3-butenyl radicals generated by photolysis of variously substituted Barton esters (both open-chain 1a-d and cyclohexyl 1e-h) with CF(2)=CCl(2) gave a mixture of cyclized products (cyclopentanes 6 and 8 and cyclohexanes 7 and 9) as well as noncyclized products (4and 5) in various ratios depending on the substitution pattern at the olefinic moiety. The product ratios of [cyclization (6 + 7 + 8 + 9):noncyclization (5)] for 1 with more alkyl substituents on the CC double bond were greater than those for 1 with fewer substituents. The products ratio of [5-exo (6 + 8):6-endo (7 + 9)] was influenced by a steric effect. Photoreaction of Barton ester 2 with CF(2)=CCl(2) gave a mixture of cyclohexanes 16 and 17 as well as noncyclized 14 and 15. Dehydrochlorination of decalins 7g and 7h followed by oxidation of sulfide and [2,3]sigmatropic rearrangement of the allyl sulfoxide gave octahydronaphthalenones 23 and 27, respectively.
