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Herein, we report the identification and preclinical profile of a lead compound 10 , ( SPR519 ) as an equally potent dual inhibitor of PI3Kα and mTOR kinases. SPR519 exhibits an EC 50 of low sub-micromolar range among various tested cancer cell lines such as A2780 (0.23 μM), PC3 (0.48 μM), and SKOV3 (0.50 μM). When administrated orally, it shows a considerably high plasma exposure (area under curve: 26,858 nM/h at 1 mg/kg) in mice. Moreover, it is found to be safe in animals with a dose of 30 mg/kg BID for 12 days in the dose tolerance study. SPR519 did not show any CYP or hERG liability. The identified lead compound demonstrates significant efficacy and bioavailability in ovarian and colon cancer xenograft models when evaluated for dose-ranging efficacy studies, at a dose as low as 2.5 mg/kg.

A new class of potent PI3Kα inhibitors is identified based on aryl substituted morpholino-triazine scaffold. The identified compounds showed not only a high level of enzymatic and cellular potency in nanomolar range but also high oral bioavailability. The three lead molecules (based on their in vitro potency) when evaluated further for in vitro metabolic stability as well as pharmacokinetic profile led to the identification of 26, as a candidate for further development. The IC50 and EC50 value of 26 is 60 and 500 nM, respectively, for PI3Kα enzyme inhibitory activity and ovarian cancer (A2780) cell line. The identified lead also showed a high level of microsomal stability and minimal inhibition activity for CYP3A4, CYP2C19, and CYP2D6 at 10 μM concentrations. The lead compound 26, demonstrated excellent oral bioavailability with an AUC of 5.2 μM at a dose of 3 mpk in mice and found to be well tolerated in mice when dosed at 30 mpk BID for 5 days.

Octaethyl porphyrin (OEP) and its Ni and Zn derivatives are considered as model compounds in biochemical, photophysical, and fossil fuel chemistry. They have thus been investigated by high-resolution solid-state (13)C NMR using powders, but peak assignment has been difficult because of large line widths. Arguing that a significant cause of broadening might be the anisotropic bulk magnetic susceptibility, we utilized single crystals in our (13)C cross-polarization magic angle spinning (CP-MAS) measurements and observed a nearly 2-fold line narrowing. This enhanced resolution enabled us to assign chemical shifts to each carbon for all the three compounds. The new assignments are now in agreement with X-ray structural data and allowed us to probe the motional dynamics of the methyl and methylene carbons of the OEP side chains. It is apparent that the use of single crystals in (13)C CP-MAS measurements has a significantly wider impact than previously thought.

The method describes a rapid and accurate procedure for the analysis of ethyl carbamate in wines. The separation of the ethyl carbamate (EC), the target analyte, from alcohol and the sample matrix is a challenge to many analytical chemists. After alcohol removal from the sample, EC was extracted and concentrated by solid-phase extraction. For analysis of EC, large-volume injection on a programmable temperature vaporization (PTV) inlet was used followed by multidimensional gas chromatography/mass spectrometry (MDGC/MS) using electron-impact ionization (EI). For quantitation, the ratio of ions produced during EI at m/z 62 (EC) and 64 (isotopically labeled EC) was monitored. The use of solid-phase extraction and MDGC/MS removes the majority of the matrix interference encountered in other methods. A linear dynamic range was established from 0.387 to 1160 ng/mL, with a limit of detection at 0.1 ng/mL and limit of quantitation at 1 ng/mL.

A novel series of arylcyclopropanecarboxyl guanidines was synthesized and evaluated for activity against the sodium hydrogen exchanger isoform-1 (NHE-1). In biological assays conducted in an AP1 cell line expressing the human NHE-1 isoform, the starting cyclopropane 3a (IC(50) = 3.5 microM) shows inhibitory activity comparable to cariporide (IC(50) = 3.4 microM). Structure-activity relationships are used to optimize the affinity of various acyl guanidines for NHE-1 by screening the effect of substituents at both aryl and cyclopropyl rings. It is demonstrated that introduction of appropriate hydrophobic groups at the phenyl ring and a gem-dimethyl group at the cyclopropane ring enhances the NHE-1 inhibitory activity by up to 3 orders of magnitude (compound 7f, IC(50) = 0.003 microM). In addition, the gem-dimethyl series of analogues seem to display improved oral bioavailability and longer plasma half-life in rats. Furthermore, the lead benzodihydrofuranyl analogue 1 (BMS-284640) shows over 380-fold increased NHE-1 inhibitory activity as well as improved selectivity for NHE-1 over NHE-2 compared to cariporide.

A series of azetidinone cholesterol absorption inhibitors related to SCH 48461 ((-)-6) has been prepared, and compounds were evaluated for their ability to inhibit hepatic cholesteryl ester formation in a cholesterol-fed hamster model. Although originally designed as acyl CoA: cholesterol acyltransferase (ACAT) inhibitors, comparison of in vivo potency with in vitro activity in a microsomal ACAT assay indicates no correlation between activity in these two models. The molecular mechanism by which these compounds inhibit cholesterol absorption is unknown. Despite this limitation, examination of the in vivo activity of a range of compounds has revealed clear structure-activity relationships consistent with a well-defined molecular target. The details of these structure-activity relationships and their implications on the nature of the putative pharmacophore are discussed.

Substituted (1,2-diarylethyl)amides have been prepared and evaluated for their ability to inhibit microsomal acyl-CoA:cholesterol acyltransferase activity in vitro and to lower hepatic cholesteryl ester content in vivo in a cholesterol-fed hamster. Simple unsubstituted (diarylethyl)amides were potent inhibitors in vitro but showed poor activity in vivo. Introduction of polar groups at specific locations on the diarylethylamine moiety decreased in vitro activity but increased in vivo activity. Both effects were highly structure dependent, suggesting specific interactions which were mediating activity in each model. Optimization of these opposing effects led to compounds which were potent in both models.