Identification of positron emission tomography ligands for NPY Y5 receptors in the brain.

A series of trans-3-oxospiro[(aza)isobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide derivatives were synthesized and profiled for NPY Y5 binding affinity, brain and CSF penetrability in rats, and susceptibility to human and mouse P-glycoprotein transporters in order to develop a PET ligand. Compound 12b exhibited an acceptable profile for a PET ligand, and [(11)C]12b was successfully utilized in clinical settings as a Y5 PET ligand.

Aryl urea derivatives of spiropiperidines as NPY Y5 receptor antagonists.

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.

Identification of novel and orally active spiroindoline NPY Y5 receptor antagonists.

A series of spiroindoline-3,4'-piperidine derivatives were synthesized and evaluated for their binding affinities and antagonistic activities at Y5 receptors. Potent Y5 antagonists were tested for their oral bioavailabilities and brain penetration in rats. Some of the antagonists showed good oral bioavailability and/or good brain penetration. In particular, compound 6e was orally bioavailable and brain penetrant, and oral administration of 6e inhibited bPP-induced food intake in rats with a minimum effective dose of 10mg/kg.

Novel orally active NPY Y5 receptor antagonists: Synthesis and structure-activity relationship of spiroindoline class compounds.

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.

Discovery of trans-N-[1-(2-fluorophenyl)-3-pyrazolyl]-3-oxospiro[6-azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide, a potent and orally active neuropeptide Y Y5 receptor antagonist.

A series of trans-3-oxospiro[(aza)isobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide derivatives were synthesized to identify potent NPY Y5 receptor antagonists. Of the compounds, 21j showed high Y5 binding affinity, metabolic stability and brain and cerebrospinal fluid (CSF) penetration, and low susceptibility to P-glycoprotein transporters. Oral administration of 21j significantly inhibited the Y5 agonist-induced food intake in rats with a minimum effective dose of 1mg/kg. This compound was selected for proof-of-concept studies in human clinical trials.

Design and synthesis of the potent, orally available, brain-penetrable arylpyrazole class of neuropeptide Y5 receptor antagonists.

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.

(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, a selective and orally active neuropeptide Y Y5 receptor antagonist.

(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.

Novel potent neuropeptide Y Y5 receptor antagonists: synthesis and structure-activity relationships of phenylpiperazine derivatives.

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.

Synthesis and evaluation of substituted 4-alkoxy-2-aminopyridines as novel neuropeptide Y1 receptor antagonists.

A series of substituted 4-alkoxy-2-aminopyridines 2, which were formally derived from neuropeptide Y1 antagonist 1 by replacing the morpholino portion with alkoxy groups, were synthesized and evaluated as neuropeptide Y Y1 receptor antagonists. Primary structure-activity relationships and identification of potent 4-alkoxy derivatives are described.