Novel potent neuropeptide Y Y5 receptor antagonists: Synthesis and structure–activity relationships of phenylpiperazine derivatives (original) (raw)
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Bioorganic & Medicinal Chemistry Letters, 2000
AbstractÐThe design of a novel series of NPY-Y 5 receptor antagonists is described. Key elements for the design were the identi®cation of weak Y 5 hits from a Y 1 program, results from a combinatorial approach and database mining. This led to the discovery of the quinazoline 4 and the aryl-sulphonamide moiety as major components of the pharmacophore for Y 5 anity. The synthesis and SAR towards CGP71683A is described. #
Synthesis and SAR of selective small molecule neuropeptide Y Y2 receptor antagonists
Bioorganic & Medicinal Chemistry Letters, 2012
Highly potent and selective small molecule Neuropeptide Y Y2 receptor antagonists are reported. The systematic SAR exploration of a hit molecule N-(4-ethoxyphenyl)-4-[hydroxy(diphenyl)methyl]piperidine-1-carbothioamide, identified from HTS, led to the discovery of highly potent NPY Y2 antagonists 16 (CYM 9484) and 54 (CYM 9552) with IC 50 values of 19 nM and 12 nM respectively.
Bioorganic & Medicinal Chemistry, 2009
A series of 2-pyridone-containing imidazoline derivatives was synthesized and evaluated as neuropeptide Y Y5 receptor antagonists. Optimization of the 2-pyridone structure on the 2-position of the imidazoline ring led to identification of 1-(difluoromethyl)-5-[(4S,5S)-4-(4-fluorophenyl)-4-(6-fluoropyridin-3-yl)-5-methyl-4,5-dihydro-1H-imidazol-2-yl]pyridin-2(1H)-one (7m). Compound 7m displayed statistically significant inhibition of food intake in an agonist-induced food intake model in SD rats and no adverse cardiovascular effects in anesthetized dogs. In addition, markedly higher brain penetrability and a lower plasma Occ90 value were observed in P-gp-deficient mdr1a (À/À) mice compared to mdr1a (+/+) mice after oral administration of 7m.
Bioorganic & Medicinal Chemistry Letters, 2009
Neuropeptide Y Y5 recepter antagonist Brain and CSF permeable Inhibition of food intake in mice Imidazoline derivatives a b s t r a c t 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 54 nM. Subsequent optimization led to the identification of several potent derivatives.
Bioorganic & Medicinal Chemistry, 2006
A series of novel 5,5-diphenylimidazolones was synthesized and evaluated for activity against the human neuropeptide Y5 receptor. The 3-pyridyl analog 46 demonstrated an IC50 of 8.3 nM with a favorable pharmacokinetic profile in rats, but was ineffective in reducing food intake.A series of novel 5,5-diphenylimidazolones was synthesized and evaluated for activity against the human neuropeptide Y5 receptor. The 3-pyridyl analog 46 demonstrated an IC50 of 8.3 nM with a favorable pharmacokinetic profile in rats, but was ineffective in reducing food intake.
ACS Medicinal Chemistry Letters, 2012
A novel class of bicyclo[3.1.0]hexanylpiperazine neuropeptide Y (NPY) Y1 antagonists has been designed and synthesized. Scatchard binding analysis showed these compounds to be noncompetitive with [ 125 I]PYY binding to the Y1 receptor. The most potent member, 1-((1α,3α,5α,6β)-6-(3-ethoxyphenyl)-3-methylbicyclo[3.1.0]hexan-6-yl)-4-phenylpiperazine (2) had an IC 50 = 62 nM and displayed excellent oral bioavailability in rat (% F po = 80), as well as good brain penetration (B/P ratio = 0.61). In a spontaneous nocturnal feeding study with male Sprague−Dawley rats, 2 significantly reduced food intake during a 12 h period.
N-Acylated α-(3-pyridylmethyl)-β-aminotetralin antagonists of the human neuropeptide Y Y5 receptor
Bioorganic & Medicinal Chemistry Letters, 2000
AbstractÐa-(3-Pyridylmethyl)-b-aminotetralins were acylated with amino-piperidinyl and-pyrrolidinyl acetic acids, and with (aminomethyl)cyclohexanecarboxylic acid. Reaction with acyl chlorides, chloroformates, and isocyanates gave amides 8e, carbamates 9, and ureas 10, which bound to the Y5 receptor with nanomolar anity. Congeners 11a and 11d containing a terminal benzimidazolone group were shown to be functional Y5 antagonists. #