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This paper describes the preclinical validation of the radioligand [11C]ORM-13070 and its tritiated analog for addressing selectivity and occupancy of the selective alpha-2C adrenergic receptor (α2CR) antagonist BAY 292 in the cynomolgus brain. BAY 292 is a novel drug candidate being developed for the treatment of obstructive sleep apnea (OSA) via binding to central α2CR. In vitro autoradiography studies with sections from non-diseased post-mortem human caudate revealed an excellent specific binding window (>80%) using [3H]ORM-13070. BAY 292 bound to the same binding site as [3H]ORM-13070 and generated a good specific binding signal, with greater selectivity for α2CR. In non-human primates in vivo, [11C]ORM-13070 demonstrated a reversible behavior, with uptake at baseline highest in striatum (putamen, caudate, ventral striatum, and pallidum) and low in the cerebellar cortex, consistent with the known distribution of the α2CR. A dose dependent increase in receptor occupancy after BAY 292 administration was observed, confirming BBB penetration and target engagement. The estimated EC50 for BAY 292 is 33.39 ± 11.91 ng/mL. This study aimed to demonstrate the suitability of [11C]ORM-13070 as a PET-radioligand for the study of α2CR in the non-human primate brain, and to pave the way for future clinical PET tracer studies with BAY 292. [ABSTRACT FROM AUTHOR]

An intramolecular N-heterocyclic carbene (NHC)-catalyzed hydroacylation of unactivated double bonds is reported. The NHC-catalyzed hydroacylation facilitated a unique C-C bond-forming reaction to afford substituted chroman-4-ones in moderate to excellent yields, even ones containing all-carbon quaternary centers.

A novel protocol is described for the palladium-catalyzed intramolecular direct arylation of benzoic acids, which has combined decarboxylation and C-H activation into one efficient process. Dibenzofuran derivatives are formed in good yield with the optimized catalyst system of palladium trifluoroacetate, silver carbonate and the proper solvent mixture (5% DMSO/dioxane).

This paper describes the preclinical validation of the radioligand [ 11 C]ORM-13070 and its tritiated analog for addressing selectivity and occupancy of the selective alpha-2C adrenergic receptor (α 2C R) antagonist BAY 292 in the cynomolgus brain. BAY 292 is a novel drug candidate being developed for the treatment of obstructive sleep apnea (OSA) via binding to central α 2C R. In vitro autoradiography studies with sections from non-diseased post-mortem human caudate revealed an excellent specific binding window (>80%) using [ 3 H]ORM-13070. BAY 292 bound to the same binding site as [ 3 H]ORM-13070 and generated a good specific binding signal, with greater selectivity for α 2C R. In non-human primates in vivo , [ 11 C]ORM-13070 demonstrated a reversible behavior, with uptake at baseline highest in striatum (putamen, caudate, ventral striatum, and pallidum) and low in the cerebellar cortex, consistent with the known distribution of the α 2C R. A dose dependent increase in receptor occupancy after BAY 292 administration was observed, confirming BBB penetration and target engagement. The estimated EC 50 for BAY 292 is 33.39 ± 11.91 ng/mL. This study aimed to demonstrate the suitability of [ 11 C]ORM-13070 as a PET-radioligand for the study of α 2C R in the non-human primate brain, and to pave the way for future clinical PET tracer studies with BAY 292., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: DPB, IP, TP and WP are employees of Bayer AG and may own shares or share options. MD was employee of Bayer AG at the time of conducting the study and data analysis. The study was funded by Bayer AG.ALA, CCC, DRB, EAR, KRZ, LAW are full-time employees of Invicro LLC.

Late-stage functionalization of lead compounds is of high interest in drug discovery since it offers an easy access to metabolites and derivatives of a lead compound without the need to redesign an often long multistep synthesis. Owing to their high degree of chemoselectivity, biocatalytic transformations, enzymatic oxidations in particular, are potentially very powerful because they could allow the synthesis of less lipophilic derivatives of a lead compound. In the majority of cases, enzymatic oxidations have been used in an empirical way as their regioselectivity is difficult to predict. In this publication, the concept of using docking/protecting groups in a biomimetic fashion was investigated, which could help steer the regioselectivity of a P450 BM3 -mediated oxidation. A novel set of docking/protecting groups was designed that can be cleaved under very mild conditions and address the often problematic aqueous solubility of the substrates. Vabicaserin was used as tool compound containing typical groups such as basic, aliphatic, and aromatic moieties. The results were rationalized with the help of in silico docking and molecular dynamic studies., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A novel protocol for the palladium-catalyzed intramolecular direct arylation of benzoic acids is reported, which combines decarboxylation and C-H activation into one efficient process. With the optimized catalyst system of palladium trifluoroacetate, silver carbonate, and the proper solvent mixture (5% DMSO/dioxane), dibenzofuran derivatives are formed in excellent yield and selectivity.

A new LDA-induced anionic N-C carbamoyl migration of 2-arylindoles (7) is reported. Treatment of N-carbamoylindoles 10 and 13, readily available by direct and ipso-borodesilylative Suzuki-Miyaura cross-coupling routes from 8 and 12, respectively, provides a general route to functionalized 2-arylindoles 11 and 14, respectively (Tables 1 and 2). The reaction has been applied to the synthesis of benzo[ a]carbazoles 16 and indeno[1,2- b]indoles 18, and its intramolecularity has been established by a crossover experiment (Scheme 4).