Eric Wellner

Oxadiazoles in medicinal chemistry.

Oxadiazoles are five-membered heteroaromatic rings containing two carbons, two nitrogens, and one oxygen atom, and they exist in different regioisomeric forms. Oxadiazoles are frequently occurring motifs in druglike molecules, and they are often used with the intention of being bioisosteric replacements for ester and amide functionalities. The current study presents a systematic comparison of 1,2,4- and 1,3,4-oxadiazole matched pairs in the AstraZeneca compound collection. In virtually all cases, the 1,3,4-oxadiazole isomer shows an order of magnitude lower lipophilicity (log D), as compared to its isomeric partner. Significant differences are also observed with respect to metabolic stability, hERG inhibition, and aqueous solubility, favoring the 1,3,4-oxadiazole isomers. The difference in profile between the 1,2,4 and 1,3,4 regioisomers can be rationalized by their intrinsically different charge distributions (e.g., dipole moments). To facilitate the use of these heteroaromatic rings, novel synthetic routes for ready access of a broad spectrum of 1,3,4-oxadiazoles, under mild conditions, are described.

Sila-haloperidol, a silicon analogue of the dopamine (D2) receptor antagonist haloperidol: synthesis, pharmacological properties, and metabolic fate.

Haloperidol (1 a), a dopamine (D2) receptor antagonist, is in clinical use as an antipsychotic agent. Carbon/silicon exchange (sila‐substitution) at the 4‐position of the piperidine ring of 1 a (R3COH → R3SiOH) leads to sila‐haloperidol (1 b). Sila‐haloperidol was synthesized in a new multistep synthesis, starting from tetramethoxysilane and taking advantage of the properties of the 2,4,6‐trimethoxyphenyl unit as a unique protecting group for silicon. The pharmacological profiles of the C/Si analogues 1 a and 1 b were studied in competitive receptor binding assays at D1–D5, σ1, and σ2 receptors. Sila‐haloperidol (1 b) exhibits significantly different receptor subtype selectivities from haloperidol (1 a) at both receptor families. The C/Si analogues 1 a and 1 b were also studied for 1) their physicochemical properties (log D, pKa, solubility in HBSS buffer (pH 7.4)), 2) their permeability in a human Caco‐2 model, 3) their pharmacokinetic profiles in human and rat liver microsomes, and 4) their inhibition of the five major cytochrome P450 isoforms. In addition, the major in vitro metabolites of sila‐haloperidol (1 b) in human liver microsomes were identified using mass‐spectrometric techniques. Due to the special chemical properties of silicon, the metabolic fates of the C/Si analogues 1 a and 1 b are totally different.

Can silicon make an excellent drug even better? An in vitro and in vivo head-to-head comparison between loperamide and its silicon analogue sila-loperamide.

Loperamide (1a), an opioid receptor agonist, is in clinical use as an antidiarrheal agent. Carbon/silicon exchange (sila‐substitution) at the 4‐position of the piperidine ring of 1a (R3COH→R3SiOH) leads to sila‐loperamide (1b). Sila‐loperamide was synthesized in a multistep procedure, starting from triethoxyvinylsilane and taking advantage of the 4‐methoxyphenyl (MOP) unit as a protecting group for silicon. The in vitro and in vivo pharmacokinetic (PK) and pharmacodynamic (PD) properties of the C/Si analogues 1a and 1b were determined and compared. Despite significant differences in the in vitro PK properties of loperamide and sila‐loperamide regarding clearance, permeability, and efflux, both compounds exhibited nearly identical in vivo PK profiles. The increase in metabolic stability of the silicon compound 1b observed in vitro seems to be counterbalanced by an increase in efflux and diminished permeability compared to the parent carbon compound 1a. Overall, sila‐loperamide exhibits high unbound clearance (CLu), leading to a significant decrease in unbound concentration (Cu) and unbound area under the curve (AUCu) after oral exposure, compared to loperamide. In vitro and in vivo metabolic studies showed an altered profile of biotransformation for the silicon compound 1b, leading to the formation of a more polar and quickly cleared metabolite and preventing the formation of the silicon analogue of the neurotoxic metabolite observed for the parent carbon compound 1a. These differences can be correlated with the different chemical properties of the C/Si analogues 1a and 1b. This study provides some of the most detailed insights into the effects of a carbon/silicon switch and how this carbon/silicon exchange affects overall drug properties.

Design of Small Molecule Inhibitors of Acetyl-Coa Carboxylase 1 and 2 Showing Reduction of Hepatic Malonyl-Coa Levels in Vivo in Obese Zucker Rats.

Inhibition of acetyl-CoA carboxylases has the potential for modulating long chain fatty acid biosynthesis and mitochondrial fatty acid oxidation. Hybridization of weak inhibitors of ACC2 provided a novel, moderately potent but lipophilic series. Optimization led to compounds 33 and 37, which exhibit potent inhibition of human ACC2, 10-fold selectivity over inhibition of human ACC1, good physical and in vitro ADME properties and good bioavailability. X-ray crystallography has shown this series binding in the CT-domain of ACC2 and revealed two key hydrogen bonding interactions. Both 33 and 37 lower levels of hepatic malonyl-CoA in vivo in obese Zucker rats.

Si- and C-Functional Organosilicon Building Blocks for Synthesis Based on 4-Silacyclohexan-1-ones Containing the Silicon Protecting Groups MOP (4-Methoxyphenyl), DMOP (2,6-Dimethoxyphenyl), or TMOP (2,4,6-Trimethoxyphenyl)

4-Silacyclohexan-1-ones 1a-1c, 4-silacyclohexan-1-one oximes 2a-2c, 1,4-azasilepan-7-ones 3a-3c, 1,4-azasilepanes 4a-4c, and 2-bromo-4-silacyclohexan-1-ones 5a and 5b were prepared in multistep syntheses, starting from trimethoxypropylsilane. All of these compounds represent C-functional (R2C═O, R2C═N-OH, R-NH(C═O)-R, R2NH, or R3C-Br) silicon-containing heterocycles that contain Si-MOP, Si-DMOP, or Si-TMOP moieties (MOP = 4-methoxyphenyl; DMOP = 2,6-dimethoxyphenyl; TMOP = 2,4,6-trimethoxyphenyl), which can be cleaved under mild conditions by protodesilylation. As a proof of principle, compounds 3a-3c were transformed quantitatively and selectively into the chlorosilane 6 (treatment with hydrogen chloride in dichloromethane). Thus, the C- and Si-functional compounds 1a-1c, 2a-2c, 3a-3c, 4a-4c, 5a, and 5b represent versatile building blocks for synthesis.

Second-generation fluorescent quadracyclic adenine analogues: environment-responsive probes with enhanced brightness.

Fluorescent base analogues comprise a group of increasingly important molecules for the investigation of nucleic acid structure, dynamics, and interactions with other molecules. Herein, we report on the quantum chemical calculation aided design, synthesis, and characterization of four new putative quadracyclic adenine analogues. The compounds were efficiently synthesized from a common intermediate through a two-step pathway with the Suzuki-Miyaura coupling as the key step. Two of the compounds, qAN1 and qAN4, display brightnesses (εΦF) of 1700 and 2300, respectively, in water and behave as wavelength-ratiometric pH probes under acidic conditions. The other two, qAN2 and qAN3, display lower brightnesses but exhibit polarity-sensitive dual-band emissions that could prove useful to investigate DNA structural changes induced by DNA-protein or -drug interactions. The four qANs are very promising microenvironment-sensitive fluorescent adenine analogues that display considerable brightness for such compounds.

Synthesis and photophysical characterisation of new fluorescent triazole adenine analogues

Fluorescent nucleic acid base analogues are powerful probes of DNA structure. Here we describe the synthesis and photo-physical characterisation of a series of 2-(4-amino-5-(1H-1,2,3-triazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl) and 2-(4-amino-3-(1H-1,2,3-triazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl) analogues via Sonogashira cross-coupling and [3 + 2]-cycloaddition reactions as the key steps in the synthesis. Compounds with a nitrogen atom in position 8 showed an approximately ten-fold increase in quantum yield and decreased Stokes shift compared to analogues with a carbon atom in position 8. Furthermore, the analogues containing nitrogen in the 8-position showed a more red-shifted and structured absorption as opposed to those which have a carbon incorporated in the same position. Compared to the previously characterised C8-triazole modified adenine, the emissive potential was significantly lower (tenfold or more) for this new family of triazoles-adenine compounds. However, three of the compounds have photophysical properties which will make them interesting to monitor inside DNA.

GPR103 Antagonists Demonstrating Anorexigenic Activity in Vivo: Design and Development of Pyrrolo[2,3-c]pyridines That Mimic the C-Terminal Arg-Phe Motif of QRFP26

GPR103, a G-protein coupled receptor, has been reported to have orexigenic properties through activation by the endogenous neuropeptide ligands QRFP26 and QRFP43. Recognizing that central administration of QRFP26 and QRFP43 increases high fat food intake in rats, we decided to investigate if antagonists of GPR103 could play a role in managing feeding behaviors. Here we present the development of a new series of pyrrolo[2,3-c]pyridines as GPR103 small molecule antagonists with GPR103 affinity, drug metabolism and pharmacokinetics and safety parameters suitable for drug development. In a preclinical obesity model measuring food intake, the anorexigenic effect of a pyrrolo[2,3-c]pyridine GPR103 antagonist was demonstrated. In addition, the dynamic 3D solution structure of the C-terminal heptapeptide of the endogenous agonist QRFP26(20-26) was determined using NMR. The synthetic pyrrolo[2,3-c]pyridine antagonists were compared to this experimental structure, which displayed a possible overlay of pharmacophore features supportive for further design of GPR103 antagonists.

Synthesis and Pharmacological Properties of Silicon-Containing GPR81 and GPR109A Agonists.

The GPR81 and GPR109A receptors mediate antilipolytic effects and are potential drug targets for the treatment of metabolic disorders such as dyslipidemia and type 2 diabetes. There is still a need to identify potent GPR81 agonists as pharmacological tools. A high‐throughput screen identified an acylurea‐based GPR81 agonist lead series, with activities at the GPR109A receptor as well. To expand the chemical scope and to explore the pharmacological and pharmacokinetic consequences, a series of structurally related organosilicon compounds with a 6‐sila‐4,5,6,7‐tetrahydrobenzo[d]thiazole skeleton was synthesized and studied for their physicochemical properties [octanol/water distribution coefficient (pH 7.4), solubility in HBSS buffer (pH 7.4)], agonistic potency at rat GPR81 and GPR109A receptors, and intrinsic clearance in human liver microsomes and rat hepatocytes. The straightforward synthesis of these organosilicon compounds offered a valuable expansion of the chemical scope in the above‐mentioned GPR81 agonist lead series, provided potency and efficacy SAR, and yielded compounds with sub‐micromolar GPR81 potency. This work supports the value of including silicon chemistry into the toolbox of medicinal chemistry.

Methods for the Construction of New Highly Functionalised Guanidines

In this study, we present a fast and chemoselective protocol to highly functionalised guanidines. Guanidines containing a hydroxy function were constructed in the microwave by regioselective ring opening of epoxides in the presence of ammonium hydroxide giving the primary amines, which then were reacted with isothiouronium salts. Direct coupling of an unsubstituted guanidine with an epoxide in the presence of n-BuLi gave the same product.