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SAR studies related to the high-throughput screening lead 4, a moderately potent antagonist of human NPY Yi receptors (K,=109 nM), have been reported (53,54). Modification of the piperazine and C3-ester functionalities afforded BMS-193885 (5), which exhibited a K, of 3.3 nM for Y, receptors (53). This compound was demonstrated to be a functional antagonist of human Yi receptors (Kb=4.5 nM), and did not have significant affinity for NPY Y2, Y4 and Y5 receptors. In rats, 5 (10 - 30 mg/kg) administered intraperitoneally (i.p.) dose-dependently inhibited NPY-induced feeding, and spontaneous nocturnal food consumption (53). Replacement of the dihydropyridine moiety by dihydropyrazine resulted in loss of Yi receptor binding affinity (54).

Taken together, the results from studies with the newer, structurally diverse, brain-penetrant NPY Yi receptor antagonists in wild-type and genetically modified rodent models confirm a role for NPY Yi receptors for mediating feeding, in particular for feeding following a fasting period.

NPY Ys Receptor Liqands - Since the late 1990's there have been numerous reports of potent NPY Y5 receptor antagonists, which have been the subject of recent reviews (55, 56). Activity in the area reflects both the high level of interest in NPY Y5 receptor antagonists as potential anti-obesity agents, and the apparent ease of identifying tractable leads suitable for optimization. While reports of new NPY Y5 receptor antagonists have slowed over the past year, there has been significant progress in the development of potent Y5 receptor antagonists with optimized pharmacokinetic properties and their evaluation in feeding models. Studies with these newer, structurally distinct compounds are important in light of recent data reported for CGP 71683A (6), one of the first potent and selective Y5 receptor antagonists. In studies that were interpreted as defining the pharmacological profile of a Y5 antagonist, 6 produced marked anorectic effects in rodent feeding models

(57). However, the Y5 receptor specificity of ni_|2 these effects has been discredited. In addition a to its affinity for Y5 receptors, 6 has high affinity for serotonergic transporters and muscarinic receptors, and inhibits food intake in NPY Y5 receptor deficient mice and NPY deficient rats & o'-^o (58,59).

Detailed characterization of the bis-aryl imidazole 7 in rat feeding models has recently been reported (60). Compound 7 displayed high affinity for human and rat NPY Y6 receptors (hY5 Kj=1.2 nM; rY5 Ki=1.7 nM) and antagonized NPY-induced Ca2+ mobilization in cells expressing the human Y5 receptor with an IC50 of 0.7 nM. In addition, 7 did not significantly bind to NPY Yi and Y2 receptors (ICSo>1 |iM), or to over 50 other receptors, ion channels and transporters (IC5o>1 nM). Compound 7 (30 mg/kg p.o.) achieved high CNS exposure in rats and inhibited food intake elicited by the Ys agonist bovine pancreatic polypeptide (bPP). At an oral dose of 40 mg/kg, 7 did not inhibit food intake in rats for a 3 h period following 24 h food deprivation, and a 30 mg/kg oral dose failed to inhibit spontaneous feeding, despite strong evidence that the compound occupies Ys receptors at these doses. It was further stated that 7 did not affect energy utilization in rats dosed at 30 mg/kg p.o. (60).

Imidazole-based Y5 receptor antagonists structurally related to 7 have independently been disclosed. Optimization of the weakly potent screening lead 8 resulted in identification of fused imidazole FR252384 (9) which displayed a K of 2.3 nM for recombinant human NPY Ys receptors (61). Compound 9 was stated to be orally bioavailable and brain penetrant but to be devoid of anorectic effects in Zucker rats.

The lack of anti-feeding effects of the imidazole 7 is consistent with studies reported for the structurally unrelated carbazole urea 10 (62,63). Compound 10 exhibited high affinity for rat and human NPY Y5 receptors (ICso=9 nM and 3 nM, respectively). Moreover, 10 did not display significant affinity for other NPY receptors or a diverse panel of unrelated receptors, enzymes or transporters. The compound was shown to be a functional antagonist of human Y5 receptors in cell-based Ca2+ flux (ICso=6 nM) and gene reporter assays (ICso=37 nM). Key steps in the discovery of 10 from a previously reported thioether lead H (Y5 ICso=350 nM) were replacement of the thioether by a carbon linker and incorporation of the carbazole anillde to confer improved potency as in 12 (Y5 ICso=2 nM), improvement of pharmacokinetic properties by replacement of the pyridyl propionamide as a morpholine urea moiety to afford 13 (Y5 ICso=7 nM), and introduction of the 4-methyl substituent to eliminate the genotoxicity of the embedded aminocarbazole fragment (62).

13 R = Y

In rat, 10 possessed good oral bioavailability (F=76%) and a half-life of 3.7 h. The csf levels of 10 approximated the free plasma concentration, consistent with favorable CNS penetration. Oral administration of 10 (3 mg/kg) blocked food intake elicited by a selective Y5 agonist, consistent with occupation of Y5 receptors by 10, but did not block NPY-stimulated food intake. Furthermore, 10 at a dose of 10 mg/kg p.o. did not attenuate feeding induced by fasting in lean Wistar rats, or spontaneous feeding in Wistar and obese Zucker rats. Compound 10 was also evaluated chronically in both normal Wistar rats, and diet-induced obese Wistar rats maintained on a high-energy diet following a dosing regimen consistent with chronic Ys receptor blockade (10 mg/kg p.o., b.i.d.). In these experiments, rats treated with 10 displayed caloric intake and body weight gain equivalent to that of vehicle-treated

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