control animals. In contrast, positive control rats that received the mixed norepinephrine/serotonin reuptake inhibitor sibutramine displayed reduced food intake and loss of body weight (63).
SAR studies on the development of the orally bioavailable, brain penetrant aryl pyrazole NPY Y5 receptor antagonist (->-14 from the screening lead 15 (hY5 Kp59 nM) have recently been published (64). Critical steps in the optimization of (-)-14 were modification of the indane carboxamide moiety to enhance affinity, and replacement of the 4-chlorophenyl moiety by 4-(2-ethylpyridinyl) to improve oral bioavailability. In a competitive binding assay employing 125I-PYY as radioligand, compound (-)-14 displayed high affinity for human NPY Ys receptors expressed in LMtk" cells (Kj=3.5 nM) and was about 7-fold more potent than its enantiomer. In addition, the compound did not show significant affinity for NPY Yi, Y2 or Y4 receptors. Compound (-1-14 blocked NPY-induced Ca2+ flux in CHO cells expressing human NPY Y5 receptors (IC5o=14 nM), confirming that it is a functional antagonist. Oral administration of (-)-14 to rats (10 and 30 mg/kg) resulted in high brain levels, but only moderate inhibition of feeding induced by the Y5 agonist bPP. Central administration of (-)-14 suppressed bPP-induced feeding, but not food intake elicited by NPY (64).
In contrast to the lack of activity of 7 and 10 in rodent models of spontaneous feeding, the benzimidazole GW438014A (16) displayed potent anorectic effects (65). In competition binding assays employing l-PYY, 16 displayed moderate affinity for recombinant NPY Y5 receptors expressed in CHO cells («¡=211 nM), and did not bind significantly to NPY Yi, Y2 and Y4 receptors (Ki>10,000 nM) or to a panel of unrelated receptors and transporters. Compound 16 reversed PYY-mediated inhibition of forskolin-induced cAMP production in HEC-1B cells expressing human NPY Y5 receptors (ICso=197 nM), confirming its antagonist properties. In rats, 16, possessed poor oral bioavailability, however a 10 mg/kg dose of 16 administered i.p. afforded brain levels approximately two-fold above the Kj. In sated rats, 16 (3 mg/kg i.p.) significantly attenuated NPY-stimulated feeding, and had no effect on unstimulated feeding. The compound (10 mg/kg i.p.) caused profound and long-lasting reduction of food intake in food-deprived rats and in normal dark cycle feeding, and was stated to be non-aversive. In addition, repeated administration of 16 (10 mg/kg i.p.) to lean and obese Zucker rats for 6 days caused a reduction in food intake and fat mass (65).
The in vivo profile of 16 is inconsistent with that of 7, 10, and (-)-14 in that only 16 blocked feeding elicited by NPY, despite strong evidence that the latter compounds antagonized NPY Y5 receptors at the doses tested. Furthermore, in contrast to 16, compounds 7 and 10 were inactive in models of spontaneous feeding. Overall, the in vivo profile of 16 parallels that of the diaminoquinazoline 6, thus a mechanism(s) for the anorectic effects of 16 unrelated to central NPY Y5 receptor antagonism appears likely.
Finally, the design of potent, selective NPY Y5 receptor antagonists from the weakly potent, non-selective lead benextramine 17 (hY5 Ki=5 nM; hYi K,=2 nM) has recently been published (66,67). Incorporation of an aryl sulfonamide connected to
a benzylic amine through an aikyl linker as a GPCR privileged structure motif resulted in 18 (hY5 «¡=123 nM) with enhanced Ys receptor affinity and selectivity. Rig id if ¡cation of the alkyl linker as a trans bis-(1,4-diaminomethylene) linker, as in 19 (hY5 «¡=8 nM), and application of high throughput synthesis techniques, resulted in an array of potent, selective Y5 receptor antagonists (66, 67). This work is significant by virtue of its influence on the discovery of several diverse series of potent and selective Y5 receptor antagonists represented by the quinazoline 6, as well as a variety of other chemotypes (56, 68-71).
Much effort in the field has been devoted to addressing the potential for Yi and Y5 antagonists to be developed for therapeutic intervention in obesity. Accumulated data supports a role for the NPY Yi receptor in modulating feeding after food deprivation and in genetically obese rodents in which NPY tone is elevated. These data suggest that centrally acting Yi receptor antagonists might be beneficial in obese patients who are dieting, formerly obese patients who have undergone substantial weight loss, or patients with complete or partial leptin deficiency. The potential for Ys antagonists as anti-obesity agents is less clear. The weight of evidence suggests that Y5 antagonists do not significantly affect natural feeding in rodents, which is consistent with the phenotype observed for the Y5 receptor knockout mouse. The well-documented stimulatory effects of selective Y5 agonists on feeding may simply reflect an artificial situation that is not physiologically relevant. Some Y5 antagonists have been reported to produce marked anorectic effects in vivo, however data supporting a Y5 receptor mediated effect is generally lacking. However, the possibility remains that there is interplay between NPY Yi, Y2, and Y5 receptor signaling in mediating the effects of NPY on energy homeostasis. Therefore Yi and Y5 receptor antagonists in combination might have a more pronounced effect on energy homeostasis than antagonism of Yi or Ys receptors alone.
Key issues remain as to whether studies of NPY receptor antagonists in rodent obesity models are relevant to common obesity in the human population, whether patient subclasses that might benefit from treatment by NPY receptor blockade can be identified, and to what extent opposing effects of multiple complementary pathways in energy homeostasis will counteract changes in body weight. Given the myriad of physiological functions of NPY, there is also the potential for mechanism-based side effects associated with NPY receptor mediated pharmacotherapy.
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