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Kenilworth, NJ, United States

Krishna G.,2015 Galloping Hill Road | Vickery D.,Forest Research Institute | Ma L.,2015 Galloping Hill Road | Yu X.,2015 Galloping Hill Road | And 4 more authors.
Journal of Clinical Pharmacology | Year: 2011

The objective of this phase 1, open-label, parallel, randomized study was to determine the effect of posaconazole on the pharmacokinetics of caspofungin and micafungin in 67 healthy subjects. Caspofungin (70 mg on day 1, 50 mg on days 2-14 once daily; 1-hour intravenous infusion) (cohort 1) or micafungin (150 mg once daily days 1-7; 1-hour IV infusion) (cohort 2) was administered alone or with posaconazole oral suspension 400 mg twice daily, on days 1 to 14 (cohort 1) or days 1 to 7 (cohort 2). Pharmacokinetic parameters, maximum plasma concentration (C max), steady-state area under the plasma concentration-time curve over the dosing interval (AUC[τ]), and time to Cmax (Tmax) were assessed. Safety assessments included adverse events, clinical laboratory tests, vital signs, and electrocardiograms. Repeated posaconazole dosing did not affect caspofungin or micafungin pharmacokinetics. Log-transformed ratio estimates of caspofungin with posaconazole Cmax and AUC(τ) were 90% and 98%, respectively, of those with caspofungin alone at day 14; ratio estimates of micafungin with posaconazole Cmax and AUC(τ) were 104% and 109%, respectively, of those with micafungin alone at day 7. Median Tmax (1 hour) did not change. Coadministration of posaconazole with caspofungin or micafungin was generally well tolerated and did not affect the pharmacokinetics of either echinocandin. © 2011 The Author(s).

Yu T.,2015 Galloping Hill Road | Tagat J.R.,2015 Galloping Hill Road | Kerekes A.D.,2015 Galloping Hill Road | Doll R.J.,2015 Galloping Hill Road | And 24 more authors.
ACS Medicinal Chemistry Letters | Year: 2010

The imidazo-[1,2-a]-pyrazine (1) is a dual inhibitor of Aurora kinases A and B with modest cell potency (IC50 = 250 nM) and low solubility (5 ?M). Lead optimization guided by the binding mode led to the acyclic amino alcohol 12k (SCH 1473759), which is a picomolar inhibitor of Aurora kinases (TdF Kd Aur A = 0.02 nM and Aur B = 0.03 nM) with improved cell potency (phos-HH3 inhibition IC50 = 25 nM) and intrinsic aqueous solubility (11.4 mM). It also demonstrated efficacy and target engagement in human tumor xenograft mouse models. © 2010 American Chemical Society.

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