Attribution of fentanyl analogue synthesis routes by multivariate data analysis of orthogonal mass spectral data.

Chemical attribution signatures (CAS) can be used to obtain useful forensic information and evidence from illicit drug seizures. A CAS is typically generated using hyphenated chemical analysis techniques and consists of a fingerprint of the by-products and additives present in a sample. Among other things, it can provide information on the sample's origin, its method of production, and the sources of its precursors. This work investigates the possibility of using multivariate CAS analysis to identify the synthetic methods used to prepare seized fentanyl analogues, independently of the analogues' acyl derivatization. Three chemists working in two labs synthesized three different fentanyl analogues, preparing each one in duplicate by six different routes. The final collection of analogues (96 samples) and two intermediates (16 + 32 samples) were analysed by GC-MS and UHPLC-HRMS, and the resulting analytical data were used for multivariate modelling. Independently of analogue structure, the tested fentanyls could be classified based on the method used in the first step of their synthesis. The multivariate model's ability to classify unknown samples was then evaluated by applying it to six new fentanyl analogues. Additionally, seized fentanyl samples was analysed and classified by the model.

Novel Chemical Series of 5-Lipoxygenase-Activating Protein Inhibitors for Treatment of Coronary Artery Disease.

5-Lipoxygenase (5-LO)-activating protein (FLAP) inhibitors have proven to attenuate 5-LO pathway activity and leukotriene production in human clinical trials. However, previous clinical candidates have been discontinued and the link between FLAP inhibition and outcome in inflammatory diseases remains to be established. We here describe a novel series of FLAP inhibitors identified from a screen of 10k compounds and the medicinal chemistry strategies undertaken to progress this series. Compound 4i showed good overall properties and a pIC50 hWBfree of 8.1 and an lipophilic ligand efficiency of 5.2. Target engagement for 4i was established in dogs using ex vivo measurement of leukotriene B4 (LTB4) levels in blood with good correlation to in vitro potency. A predicted human dose of 280 mg b.i.d. suggests a wide margin to any identified in vitro off-target effects and sufficient exposure to achieve an 80% reduction of LTB4 levels in humans. Compound 4i is progressed to preclinical in vivo safety studies.

Identification of Mineralocorticoid Receptor Modulators with Low Impact on Electrolyte Homeostasis but Maintained Organ Protection.

The mechanism-based risk for hyperkalemia has limited the use of mineralocorticoid receptor antagonists (MRAs) like eplerenone in cardio-renal diseases. Here, we describe the structure and property-driven lead generation and optimization, which resulted in identification of MR modulators ( S)-1 and ( S)-33. Both compounds were partial MRAs but still demonstrated equally efficacious organ protection as eplerenone after 4 weeks of treatment in uni-nephrectomized rats on high-salt diet and aldosterone infusion. Importantly, and in sharp contrast to eplerenone, this was achieved without substantial changes to the urine Na+/K+ ratio after acute treatment in rat, which predicts a reduced risk for hyperkalemia. This work led to selection of ( S)-1 (AZD9977) as the clinical candidate for treating MR-mediated cardio-renal diseases, including chronic kidney disease and heart failure. On the basis of our findings, we propose an empirical model for prediction of compounds with low risk of affecting the urinary Na+/K+ ratio in vivo.

Discovery of (3-(4-(2-Oxa-6-azaspiro[3.3]heptan-6-ylmethyl)phenoxy)azetidin-1-yl)(5-(4-methoxyphenyl)-1,3,4-oxadiazol-2-yl)methanone (AZD1979), a Melanin Concentrating Hormone Receptor 1 (MCHr1) Antagonist with Favorable Physicochemical Properties.

A novel series of melanin concentrating hormone receptor 1 (MCHr1) antagonists were the starting point for a drug discovery program that culminated in the discovery of 103 (AZD1979). The lead optimization program was conducted with a focus on reducing lipophilicity and understanding the physicochemical properties governing CNS exposure and undesired off-target pharmacology such as hERG interactions. An integrated approach was taken where the key assay was ex vivo receptor occupancy in mice. The candidate compound 103 displayed appropriate lipophilicity for a CNS indication and showed excellent permeability with no efflux. Preclinical GLP toxicology and safety pharmacology studies were without major findings and 103 was taken into clinical trials.

Novel MCH1 receptor antagonists: a patent review.

INTRODUCTION: The cyclic neuropeptide melanin-concentrating hormone (MCH) shows appetite-stimulating effects indicating an involvement in obesity. Large efforts have been invested in discovery programs to identify novel MCH1 receptor (MCHR1) antagonists. Other indications where MCHR1 antagonists may have a potential use include: anxiety/depression and, more recently, inflammatory responses in the gastrointestinal tract. AREAS COVERED: The current review covers the patent literature on MCHR1 antagonists published from November 2010 to March 2014. The applications have been grouped by filing company, and weight has been put on commenting compounds with disclosed in vivo biological data. EXPERT OPINION: Achieving sufficient separation of the human EtheR-a-Go-go channel has prevented many programs from reaching the clinic. For clinical programs, CNS exposure seems to have been a major challenge. Although clinical studies of MCHR1 antagonists have not been able to conclusively evaluate the concept, the body of evidence suggesting a role for MCHR1 antagonists in weight management is strong and novel chemical series still appear in the patent literature. An MCHR1 antagonist with the appropriate physical chemical properties is needed to convincingly evaluate the MCHR1 concept for obesity treatment and, as knowledge from previous programs are shared, the discovery of such a compound should be achievable.

Sequential one-pot bimetallic Ir(III)/Pd(0) catalysed mono-/bis-alkylation and spirocyclisation processes of 1,3-dimethylbarbituric acid and allenes.

Microwave assisted indirect functionalization of alcohols with 1,3-dimethylbarbituric acid followed by spirocyclisation employing a sequential one-pot Ir(III)/Pd(0) catalysed process, involving the formation of three new C-C bonds, one spirocyclic ring and one di- or tri-substituted exocyclic alkene, is described.

Efficient solvent-free selective monoalkylation of arylacetonitriles with mono-, bis-, and tris-primary alcohols catalyzed by a Cp*Ir complex.

Our objectives were to develop catalytic atom-economic processes accessing and/or incorporating versatile functionality using aryl/heteroaryl acetonitriles as substrates. We report essentially solvent-free [Cp*IrCl2]2 catalyzed redox neutral processes whereby substituted acetonitriles react with primary alcohols to deliver monosubstituted aryl/heteroaryl acetonitriles in excellent yield. We further demonstrate that such processes can be achieved by conventional or microwave heating and that bis- and tris-primary alcohols are also processed efficiently.