Compound was synthesized starting from cyclopropyl glycine

Compound was synthesized starting from α-cyclopropyl glycine (). After protection of the free amine via methyl carbamate and esterification to the methyl ester, the pyrrolidine core was furnished by condensation with methyl acrylate under basic conditions. Double deprotonation of the pyrrolidine followed by benzylation with the appropriate benzyl halide exclusively on the more nucleophilic carbon gave the fully elaborated quarternary center. Decarboxylation and vinylamine formation gives the cyclization partner for the aminopyrazole, which was accomplished under similar conditions described above. Finally, the methyl carbamate was removed under acidic conditions to afford the desired product. Up to now we were able to increase receptor agonist efficacy and metabolic stability of the series. Further SAR work was aimed toward improving on the poor solubility profile of the scaffold. We noted that small substituents in position 2 were tolerated (), and while ionizable groups were deleterious to activity (data not shown), a hydroxymethylene group seemed beneficial for agonist efficacy (entry ). For the first time we encountered a atpase inhibitor with measurable solubility (58μM at pH 6.8) in the series. Moreover, a small polarity change going from a trifluoromethyl-phenyl to a trifluoromethyl-pyridyl substituent in position 3 was also tolerated. Both findings combined (entry ) led to a further improvement of the scaffolds physicochemical properties and further improved the solubility of the compound. Unfortunately, we saw a 10 fold decrease in functional potency in an in vitro GLP1 secretion assay using GLUTag cells. As expected, the hydroxymethylene group also posed a considerable metabolic liability, which is reflected in the high ERs of these analogs. Blocking of the metabolic softspot with compounds such as reduced extraction ratio values, but also GPR119 activity. An attempt to slow down metabolism via deuteration of the benzylic position (entries and ) or replacement with a primary amide (entry ) failed to show the desired impact on extraction ratios and exposures. Replacement of the carboxylate with a cyclopropyl group as described above did not favorably affect metabolic stability either in this case (entries and ), and introduced additional Cyp inhibition and induction issues. Based on the overall acceptable profile, we elected compound to assess its ability to elevate GLP1 in mice acutely in vivo, as well as test its effects on glucose excursion in a 7day OGTT study in rats (A). After a onetime 10mg/kg dose, we observed a significant increase of active GLP1 by 29% in mice. After two weeks of once-a-day dosing in ZDF fa/fa rats, we also saw a clear trend in glucose reduction (up to 37% at the 30mg/kg dose level) following a glucose bolus (B for glucose time course, C for glucose AUC). In conclusion, we set out to optimize compound , a partial GPR119 agonist that does not fall into the usual GPR119 pharmacophore. Rigidification to a tricyclic system yielded potent full agonists, albeit with a further deterioration of the scaffolds poor physicochemical properties and metabolic stabilities. However, the increased potency level allowed us to implement several changes addressing both poor solubility and metabolic stability while staying in the acceptable activity range on the receptor. We learned that walking into the hydrophobic trap may not always have to be avoided at all costs, but sometimes it can open doors to previously-unacceptable derivatizations in the scaffold. We achieved a remarkable >4 log unit drop in log values going from analog to analog without loss of efficacy on the receptor, leading to measurable solubility in the series. Unfortunately, the most potent compounds with the highest solubilities did not show markedly improved metabolic stabilities and were only moderately exposed in rodents. Nevertheless, in addition to robust GLP1 elevation in mice we also observed a clear trend in glucose reduction in a 2week OGTT model in rats, rendering this series a rare GPR119 agonist scaffold outside the typical GPR119 pharmacophore displaying the desired in vivo effects in rodents.