[(Ph)₃PBr][Br₇], [(Bz)(Ph)₃P]₂[Br₈], [(<i>n</i>-Bu)₃MeN]₂[Br₂₀], [C₄MPyr]₂[Br₂₀], and [(Ph)₃PCl]₂[Cl₂I₁₄]: Extending the Horizon of Polyhalides via Synthesis in Ionic Liquids

The five polyhalides [(Ph)₃PBr][Br₇], [(Bz)(Ph)₃P]₂[Br₈], [(<i>n</i>-Bu)₃MeN]₂[Br₂₀], [C₄MPyr]₂[Br₂₀] ([C₄MPyr] = <i>N</i>-butyl-<i>N</i>-methylpyrrolidinium), and [(Ph)₃PCl]₂[Cl₂I₁₄] were prepared by the reaction of dibromine and iodine monochloride in ionic liquids. The compounds [(Ph)₃PBr][Br₇] and [(Bz)(Ph)₃P]₂[Br₈] contain discrete pyramidal [Br₇]⁻ and Z-shaped [Br₈]^2– polybromide anions. [(<i>n</i>-Bu)₃MeN]₂[Br₂₀] and [C₄MPyr]₂[Br₂₀] exhibit new infinite two- and three-dimensional polybromide networks and contain the highest percentage of dibromine ever observed in a compound. [(Ph)₃PCl]₂[Cl₂I₁₄] also consists of a three-dimensional network and is the first example of an infinite polyiodine chloride. All compounds were obtained from ionic liquids as the solvent that, on the one hand, guarantees for a high stability against strongly oxidizing Br₂ and ICl and that, on the other hand, reduces the high volatility of the molecular halogens

Discovery and translation of a target engagement marker for AMP-activated protein kinase (AMPK) - Fig 1

<p><b>A</b> AMPK Thr¹⁷²-phosphorylation in L6 myoblast after stimulation with 1μM compound 2 and western blot densitometry of 3 independent experiments <b>B</b> AMPK phosphorylation in human PBMCs after stimulation with 10μM compound 2. Bars represent the mean +/- SEM of three independent experiments of the fluorescent analysis with stimulated PBMCs from different donors. Signals on western blot are representative for 2 donors and illustrated in false colors.</p

Concentration-response curves for compound 2 in human whole blood of 4 healthy volunteers.

<p>Expression values are normalized to the expression of 4 reference genes (ACTB, GAPDH, POL2RA, HPRT1). Normalized gene expression is expressed in reporter code counts (RCC) as mean ± SEM relative to DMSO-treated samples (10⁻⁹ value). Concentration-dependent regulation of <b>A</b> GPNMB <b>B</b> RHOB <b>C</b> PGLYRP1 and <b>D</b> S100A9.</p

Overlap of consistently AMPK-regulated genes in whole blood samples from HanWistar rats after subchronic treatment and from human after 6h <i>ex vivo</i> treatment.

<p>Genes have been ranked according to the total DGE score.</p

Discovery of <i>N</i>‑[Bis(4-methoxyphenyl)methyl]-4-hydroxy-2-(pyridazin-3-yl)pyrimidine-5-carboxamide (MK-8617), an Orally Active Pan-Inhibitor of Hypoxia-Inducible Factor Prolyl Hydroxylase 1–3 (HIF PHD1–3) for the Treatment of Anemia

The discovery of novel 4-hydroxy-2-(heterocyclic)­pyrimidine-5-carboxamide inhibitors of hypoxia-inducible factor (HIF) prolyl hydroxylases (PHD) is described. These are potent, selective, orally bioavailable across several species, and active in stimulating erythropoiesis. Mouse and rat studies showed hematological changes with elevations of plasma EPO and circulating reticulocytes following single oral dose administration, while 4-week q.d. po administration in rat elevated hemoglobin levels. A major focus of the optimization process was to decrease the long half-life observed in higher species with early compounds. These efforts led to the identification of <b>28</b> (MK-8617), which has advanced to human clinical trials for anemia

1,3,8-Triazaspiro[4.5]decane-2,4-diones as Efficacious Pan-Inhibitors of Hypoxia-Inducible Factor Prolyl Hydroxylase 1–3 (HIF PHD1–3) for the Treatment of Anemia

The discovery of 1,3,8-triazaspiro[4.5]­decane-2,4-diones (spirohydantoins) as a structural class of pan-inhibitors of the prolyl hydroxylase (PHD) family of enzymes for the treatment of anemia is described. The initial hit class, spirooxindoles, was identified through affinity selection mass spectrometry (AS-MS) and optimized for PHD2 inhibition and optimal PK/PD profile (short-acting PHDi inhibitors). 1,3,8-Triazaspiro[4.5]­decane-2,4-diones (spirohydantoins) were optimized as an advanced lead class derived from the original spiroindole hit. A new set of general conditions for C–N coupling, developed using a high-throughput experimentation (HTE) technique, enabled a full SAR analysis of the spirohydantoins. This rapid and directed SAR exploration has resulted in the first reported examples of hydantoin derivatives with good PK in preclinical species. Potassium channel off-target activity (hERG) was successfully eliminated through the systematic introduction of acidic functionality to the molecular structure. Undesired upregulation of alanine aminotransferese (ALT) liver enzymes was mitigated and a robust on-/off-target margin was achieved. Spirohydantoins represent a class of highly efficacious, short-acting PHD1–3 inhibitors causing a robust erythropoietin (EPO) upregulation in vivo in multiple preclinical species. This profile deems spirohydantoins as attractive short-acting PHDi inhibitors with the potential for treatment of anemia

Discovery of a Potent and Selective DGAT1 Inhibitor with a Piperidinyl-oxy-cyclohexanecarboxylic Acid Moiety

We report the discovery of a novel series of DGAT1 inhibitors in the benzimidazole class with a piperdinyl-oxy-cyclohexanecarboxylic acid moiety. This novel series possesses significantly improved selectivity against the A_2A receptor, no ACAT1 off-target activity at 10 μM, and higher aqueous solubility and free fraction in plasma as compared to the previously reported pyridyl-oxy-cyclohexanecarboxylic acid series. In particular, <b>5B</b> was shown to possess an excellent selectivity profile by screening it against a panel of more than 100 biological targets. Compound <b>5B</b> significantly reduces lipid excursion in LTT in mouse and rat, demonstrates DGAT1 mediated reduction of food intake and body weight in mice, is negative in a 3-strain Ames test, and appears to distribute preferentially in the liver and the intestine in mice. We believe this lead series possesses significant potential to identify optimized compounds for clinical development