Identification of pyrazolo-pyrimidinones as GHS-R1a antagonists and inverse agonists for the treatment of obesity

Abstract

A pyrazolo-pyrimidinone based series of growth hormone secretagogue receptor type 1a (GHS-R1a) antagonists and inverse agonists were identified using a scaffold hop from known quinazolinone GHS-R1a modulators. Lipophilicity was reduced to decrease hERG activity while maintaining GHS-R1a affinity.SAR exploration of a piperidine substituent was used to identify small cyclic groups as a functional switch from partial agonists to neutral antagonists and inverse agonists. A tool compound was identified which had good overall properties and sufficient oral plasma and CNS exposure to demonstrate reduced food intake in mice through a mechanism involving GHS-R1a.

New Perspectives on the Development of Antiobesity Drugs

“…GSK-1614343, a ghrelin antagonist, was shown to be able to increase food intake and BW, effects abolished in the ghrelin receptor null mice [78]. Another antagonist, YIL-870 (compound (13), Table 4), was reported to significantly reduce BW and food intake in DIO mice [79] as well as, unexpectedly, on ghrelin receptor KO mice [80]; on the other hand, a derivative of this compound (inverse agonist), compound (14), Table 4, was active in WT but not on ghrelin receptor KO mice [80]. Given the structural similarity of these compounds, this effect is rather surprising, and hitherto unexplained.…”

“…in food intake (mice); shows activity in ghrelin receptor KO mice [79,80] Red. in food intake (mice); no activity in ghrelin receptor KO mice [80] KO: Knockout.…”

2-Aminoalkyl nicotinamide derivatives as pure inverse agonists of the ghrelin receptor

“…Thus, S-isomer substitution was employed in subsequent SAR studies. Although the pyrazole ring was replaced successfully by a substituted pyridine ring (15), low solubility prevented us from assessing this compound further. Recent reports have indicated that the success of potential drugs correlated with a lower aromatic ring count and a higher fractional sp3 content.…”

“…1). [15][16][17] We performed high-throughput screening (HTS) using the 125 I-ghrelin substitution assay system to obtain ghrelinR binders and the hits obtained were evaluated using an inverse agonist assay employing a reporter-gene system. This system was based on the fact that ghrelinR-derived Ga q signaling results in activation of the nuclear factor of activated T-cells (NFAT) and activator protein-1 (AP-1) response element, stimulating gene expression.…”

“…Interestingly, this 2-aminoalkyl nicotinamide structure showed no functional switching toward neutral antagonism or partial agonism (or even partial inverse agonism 24 ) in the entire SAR study, in contrast to the functional switching to partial agonism reported for many ghrelinR antagonists and inverse agonists with small structural modifications. 13,15,17 The concentration-response relationships of inverse agonists in the reporter-gene assay are depicted in Figure 3. A known peptidic ghrelinR inverse agonist, named substance P analog 14 ([D-Arg 1 , D-Phe 5 , D-Trp 7,9 , Leu 11 ]-substance P), almost completely suppressed the constitutive activity of this receptor, although its potency (IC 50 = 250 nM) was lower than the previously reported one for an inositol phosphate turnover assay 25 (IC 50 = 5.2 nM).…”