Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • Starting from commercially available dioxaspiro decan

    2021-10-14

    Starting from commercially available 1,4-dioxaspiro[4.5]decan-8-ol, was prepared by the synthetic sequence illustrated in . Aromatic nucleophilic substitution of 1,4-dioxaspiro[4.5]decan-8-ol, followed by an GDC-0994 catalyzed deprotection efficiently gave . A - enriched mixture of (/=∼3/2) was obtained from the NaBH reduction, which was separated efficiently to afford isomerically pure (>98%) and material on >100g scale. The separation was carried out by an initial crystallization, followed by trituration with acetone. Stepwise reduction of the pyridinium salt of subsequently offered the key intermediate, -4-((1-methylpiperidin-4-yl)oxy)cyclohexanol (). The final intermediate was straightforwardly prepared by nucleophilic substitution, copper promoted sulfonylation, and de-methylation. Intermediate was then converted to via a standard carbamate formation. More extensive characterization entailed expanded in vitro screening and pharmacokinetic analysis. Compound was found to maintain agonist activity at canine, monkey, and mouse GPR119 receptors (6.1nM, 144%; 3.4nM, 73%; 20.5nM, 130%, respectively). It was stable in liver microsomes across species (human, rat, mouse half-life () >60min), and also demonstrated good stability in human hepatocytes ( >120min). It was highly bound to both human and rat plasma proteins (human 97.5%, rat 96.0%), but less so for mouse (93.5%). In a subsequent Sprague-Dawley rat PK study, exhibited a low systemic clearance and low steady-state volume of distribution, while possessing excellent systemic exposure, terminal half-life, and oral bioavailability (). In an abbreviated CNS study, demonstrated a brain to plasma (b/p) ratio of approximately 1 (brain 820ng/g, plasma 841ng/mL) at 2h post-dose, indicating virtually unrestricted blood-brain barrier (BBB) penetration. In vivo GPR119 activation and corresponding glucose control was assessed for in normoglycemic 129SVE mice after oral administration ( and a). Since GIP release is expected upon activation of GPR119, plasma GIP levels were measured 45min post compound administration (). Two different doses of were administered and demonstrated a significant increase in GIP levels relative to vehicle treated controls. The 30mg/kg dose was as efficacious as our tool compound (AR231453) in this study. In an acute oral glucose tolerance test (oGTT), was dosed orally 30min prior to glucose challenge and blood glucose levels were measured over 120min time course (a). Notably, all three doses produced an equivalent response as that observed for a 3mg/kg dose of a representative DPP-4 inhibitor (Sitagliptin), and glycemic suppression relative to vehicle was approximately 40% in an area under curve (AUC) analysis. Acute glucose control was also evaluated in Zucker Diabetic Fatty (ZDF) rats (b). Compound was administered 60min prior to glucose challenge and demonstrated markedly reduced blood glucose levels in a dose-dependent manner. It showed comparable efficacy to a 3mg/kg dose of Sitagliptin when dosed at a 3 and 10mg/kg dose (43% and 58% relative to 57% (Sitagliptin) in an AUC analysis). With encouraging acute in vivo data, we investigated the effect of chronic treatment in Zucker Diabetic Fatty (ZDF) rats (). Compound was dosed once daily over 4weeks, and fed glucose and HbA1c levels were measured at the time of dosing. demonstrated a significant fed glucose lowering effect after 2weeks treatment (a) and markedly improved glycated hemoglobin (HbA1c) levels at day 28 in a dose-dependent manner (1.63%, 1.85%, and 2.58% relative to vehicle) (b). Furthermore, no loss of the acute drug response over the study period was observed, thus validating chronic use of a selective GPR119 agonist for glucose control. Lastly, we did not observe any significant drug effect on body weight irrespective GDC-0994 of dose. Further characterization of revealed no interaction at the hERG channel in either the [H]-Astemizole binding assay (IC >1000μM) or patch clamp assay (IC >30μM). In human hepatic microsomal cytochrome P450s, exhibited no significant inhibition of any of the five major isoforms (2C9, 27.5μM; 2C19, 23.4μM; 1A2, 3A4, and 2D6, >50μM) and no inhibitory activity in CYP time-dependent inhibition (/) assay. Glutathione (GSH) conjugates were not detected in the GSH trapping assay, indicating no apparent metabolite-mediated hepatotoxicity. Further, showed no cytotoxic potential in an Essential Cell Function (ECF) panel measuring sensitive cellular parameters in live HepG2 cells.