Identification of novel and orally active spiroindoline NPY Y5 receptor antagonists (original) (raw)
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Aryl urea derivatives of spiropiperidines as NPY Y5 receptor antagonists
Bioorganic & Medicinal Chemistry Letters, 2009
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 0 -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 3 mg/kg. In addition, this compound was efficacious in decreasing body weight in diet-induced obese mice.
Bioorganic & Medicinal Chemistry, 2009
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. j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / b m c 1/2) to give 2a (123 mg, 70%) as a white solid. 2a was treated with 4 N HCl in AcOEt to afford 2a HCl salt: 1 H NMR (300 MHz; CD 3 OD): d 8.75 (1H, d, J = 5.4 Hz), 8.62 (1H, t, J = 7.7 Hz), 8.38 (1H, d, J = 8.1 Hz), 7.98-7.93 (1H, m), 7.92 (2H, d, J = 9.0 Hz), 7.78 (2H, d, J = 9.0 Hz), 7.39 (1H, d, J = 8.3 Hz), 7.22-7.29 (2H, m), 7.09 (1H, t, J = 7.7 Hz), 4.26 (2H, d, J = 13.2 Hz), 3.99 (2H, s), 3.18 (2H, t, J = 13.0 Hz), 2.99 (3H, s), 2.05-1.94 (2H, m), 1.83 (2H, d, J = 13.6 Hz); HRMS (ESI + ) m/z [M+H] + 463.1806 (C 25 H 27 N 4 O 3 S requires: 463.1804).
Discovery of potent and selective small molecule NPY Y5 receptor antagonists
Bioorganic & Medicinal Chemistry Letters, 2002
The discovery of a new class of sulfonamide NPY Y5 receptor antagonists is described. Optimization of this series led to the identification of compounds with high affinity for the hY5 subtype and excellent selectivity over the other NPY receptor subtypes. The SAR for this series was examined and a model for understanding the ligand-receptor interactions was developed. # 2002 Elsevier Science Ltd. All rights reserved.
Discovery and evaluation of pyrazolo[1,5-a]pyrimidines as neuropeptide Y1 receptor antagonists
Bioorganic & Medicinal Chemistry Letters, 2011
A novel series of pyrazolo[1,5-a]pyrimidine derivatives was synthesized and evaluated as NPY Y1R antagonists. High binding affinity and selectivity were achieved with C3 trisubstituted aryl groups and C7 substituted 2-(tetrahydro-2H-pyran-4-ylamino)ethylamine moieties. Efforts to find close analogs with low plasma clearance in the rat and minimal p-glycoprotein efflux in the mouse were unsuccessful. Compound 2f (CP-671906) inhibited NPY-induced increases in blood pressure and food intake after iv and icv administration, respectively, in Sprague-Dawley (SD) rat models. Oral administration of compound 2f resulted in a modest, but statistically significant, reduction in food intake in a Wistar rat model of feeding behavior. Small inhibitions of food intake were also observed in an overnight fasting/refeeding model in SD rats. These data suggest a potential role for Y1R in the regulation of food intake in rodents.
Contemporary Development In NPYY5 Receptor Antagonist
The Internet Journal of Pharmacology, 2009
The prevalence of obesity continues to increase throughout the world and the burden of obesity and related co morbidities is large. Contemporary consideration has focused on physiology of neuropeptide Y and its role in the regulation of energy homeostasis. The data obtained to date with these newly developed tools suggests that neuropeptide Y receptor antagonists, particularly neuropeptide YY5 receptor antagonist, have potentiality to bless the obesity patients worldwide. However, the redundancy of the neurochemical systems regulating energy homeostasis may limit the effect of ablating a single pathway. New leads are under research by major pharmaceutical companies to limit the side effects and explore the area to meet clinical requirement.
L-152,804: Orally Active and Selective Neuropeptide Y Y5 Receptor Antagonist
Biochemical and Biophysical Research Communications, 2000
Previous publications indicate that the Y5 receptor may represent one of these postulated hypothalamic "feeding" receptors. Using a potent and orally available Y5 antagonist L-152,804, we evaluated the involvement of the Y5 receptor in feeding regulation.
Journal of Medicinal Chemistry, 2006
We have previously shown [Cys-Trp-Arg-Nva-Arg-Tyr-NH 2 ] 2 , 1, to be a moderately selective neuropeptide Y (NPY) Y 4 receptor agonist. Toward improving the selectivity and potency for Y 4 receptors, we studied the effects of dimerizing H-Trp-Arg-Nva-Arg-Tyr-NH 2 using various diamino-dicarboxylic acids containing either di-, tri-, or tetramethylene spacers. These parallel dimers, 2A, 2B, 3, 4A, and 4B, and the corresponding linear tandem dimer and trimer analogues, 5 and 6, had enhanced selectivity and affinity for Y 4 receptors compared to 1 ( ). Substitution of Trp and Nva with Tyr and Leu, respectively, as in 2,7-D/Ldiaminosuberic acid derivatized dimer, 7, resulted in a superior Y 4 selective agonist with picomolar affinity. Intraperitoneal (ip) injection of 7 potently inhibited food intake in fasted mice. Moreover, 7 (ip) inhibited the food intake in wild-type mice and not in Y 4 -/knock-out mice, confirming that the actions of 7 on food intake are not due to global effects, but specifically mediated Y 4 receptors.
Design, synthesis and SAR of a novel series of benzimidazoles as potent NPY Y5 antagonists
Bioorganic & Medicinal Chemistry Letters, 2010
A novel class of benzimidazole NPY Y5 receptor antagonists was prepared exploiting a privileged spirocarbamate moiety. The structure-activity relationship of this series and efforts to achieve a profile suitable for further development and an appropriate pharmacokinetic profile in rat are described. Optimisation led to the identification of the brain penetrant, orally bioavailable Y5 antagonist 9b which significantly inhibited the food intake induced by a Y5 selective agonist with a minimal effective dose of 30 mg/kg po.
Bioorganic & Medicinal Chemistry, 2006
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.