Discovery and Optimization of a Series of Carbazole Ureas as NPY5 Antagonists for the Treatment of Obesity

Abstract

The hypothesis that antagonists of the neuropeptide Y5 receptor would provide safe and effective appetite suppressants for the treatment of obesity has prompted vigorous research to identify suitable compounds. We discovered a series of acylated aminocarbazole derivatives (e.g., 3a) that are potent and selective Y5 antagonists, representing interesting starting points but suffering from poor bioavailability and concerns about potential toxicity as a consequence of the embedded aminocarbazole fragment. It proved relatively easy to improve the drug metabolism and pharmacokinetic (DMPK) properties by variation of the side chain (as in 4a) but difficult to eliminate the aminocarbazole fragment. For compounds in this series to have the potential to be drugs, we believed that both the compound itself and the component aniline must be free of mutagenic activity. Parallel structure-activity relationship studies looking at the effects of ring substitution have proved that it is possible by incorporation of a 4-methyl substituent to produce carbazole ureas with potent Y5 activity, comprised of carbazole anilines that in themselves are devoid of mutagenic activity in the Ames test. Compound 4o (also known as NPY5RA-972) is highly selective with respect to Y1, Y2, and Y4 receptors (and also to a diverse range of unrelated receptors and enzymes), with an excellent DMPK profile including central nervous system penetration. NPY5RA-972 (4o) is a highly potent Y5 antagonist in vivo but does not block neuropeptide Y-induced feeding nor does it reduce feeding in rats, suggesting that the Y5 receptor alone has no significant role in feeding in these models.

Selective Antagonism of the NPY Y5 Receptor Does Not Have a Major Effect on Feeding in Rats

“…This compound is central nervous system (CNS) penetrant, and an oral dose of 10 mg/kg NPY5RA-972 to rats produced concentrations in cerebrospinal fluid that greatly exceeded the in vitro IC 50 (inhibitory concentration 50%). Indeed, at doses to rats as low as 1 mg/kg, NPY5RA-972 inhibited feeding induced by intracerebroventricular (ICV) administration of a selective NPY Y5 agonist ([cPP [1][2][3][4][5][6][7] ,NPY 19 -23 , Ala 31 ,Aib 32 ,Gln 34 ]-hPP). However, in the dose range 1-10 mg/kg, NPY5RA-972 had no significant effect on food intake in Wistar rats induced to feed by either ICV NPY or 24 h fasting or in free-feeding Wistar or obese Zucker rats.…”

“…In particular, the importance of NPY Y5 has been suggested by the parallel pharmacology of the receptor in vitro and feeding in rodents (17)(18)(19)(20)(21)(22)(23)(24), and the inhibitory effects of NPY Y5 receptor antisense oligonucleotides (25)(26)(27)(28), NPY Y5 deficiency (29), and an NPY Y5 antagonist (30) on NPY-induced feeding in rodents. We investigated the role the NPY Y5 receptor in feeding in the rat using a previously described peptidic NPY Y5 selective agonist [cPP [1][2][3][4][5][6][7] ,NPY 19 -23 ,Ala 31 ,Aib 32 ,Gln 34] -hPP (20) and a novel, small molecular weight, potent, and selective NPY Y5 antagonist (9-isopropyl-4-methyl-3-(4-morpholinecarbonylamino)-9H-carbazole, termed NPY5RA-972) (31). The data described herein argue that, contrary to many previous data, NPY Y5 is not a significant regulator of feeding behavior in the rat.…”

Dimethyl 6-Amino-1-methyl-9H-carbazole-2,3-dicarboxylate

“…Whereas catalytic hydrogenation with gaseous hydrogen is a well-established method also for the reduction of nitrocarbazoles into aminocarbazoles (see, for example [12,13]), employment of a solid or liquid hydrogen source has the advantage of safer handling and easier reaction monitoring, especially if elevated temperatures are required. Such protocols, known as catalytic transfer hydrogenation have also been used in the nitrocarbazole series, and the combination of palladium/carbon as catalyst and hydrazine hydrate as hydrogen source had been found to be particularly useful for this purpose [14], as the yields are generally high and there are no non-volatile reagents or by-products involved.…”

Neuropeptide Y Receptor Selective Ligands in the Treatment of Obesity

“…In a study (208) using both Y 1 (120562A, BIBO 3304) and Inhibited spontaneous food intake, fasted food intake, freefeeding or NPY-induced feeding in rats (162)(163)(164)(165)(166)(167)(168)(169)(170)(171)(172)(173)(174)(175) Y 5 receptor 2-͓4-(8-methyl-2-oxo-4H-benzo͓d͔͓1,3͔oxazin-1-yl)piperidin-1-yl͔-N-(9-oxo-9H-fluoren-3-yl)acetamide 5p (188), CGP 71683A (197)(198)(199) Inhibited spontaneous food intake, fasted food intake, freefeeding rats or NPY-induced food intake in rats (188,197,198) and guinea pigs (199) GW438014A (200) FMS586 (201) Decreased weight gain rate and fat mass in rodents (200), induced acute and robust feeding responses in satiated rats (201) NPY5RA-972 (209,210) No effect on NPY-induced feeding (209, 210) Compound (Ϫ)-7, (features 2,3-dihydro-1H-yclopenta͓a͔naphthalene moiety͔ (202) Inhibited Y 5 agonist bovine PP-induced food intake in rat, no effect on NPY-induced feeding (202) JCF 104, JCF 109 (208) Reduced hyperphagic effect of NPY (208) ͓cPP1-7, NPY19 -23, Ala31,Aib32, Q34͔hPP (215) Stimulated food intake in rats (215) (199). Interestingly, the effect of the antagonists tended to cause different feeding behavior.…”