Andreas Ritzén

The potential therapeutic use of phosphodiesterase 10 inhibitors

The discovery of the enzyme phosphodiesterase 10A (PDE10A) was reported simultaneously in 1999 by three independent groups. PDE10A has been shown by localisation studies to have the most restricted distribution of all the 11 known PDE families, with the PDE10A mRNA highly expressed only in the brain and testes. In the brain, mRNA and protein are highly enriched in the striatum and, together with increased pharmacological characterisation, this unique distribution of PDE10A in the brain indicates a potential use of PDE10A inhibitors for treating neurological and psychiatric disorders, in particular, psychotic disorders like schizophrenia. However, PDE10A inhibitors have also been claimed to be useful as treatment for cancer, diabetes and especially obesity. Two years after the reported discovery of PDE10A, Bayer filed the first patent application claiming PDE10A inhibitors, followed shortly thereafter by Pfizer. Since then, a number of scientific publications and filed patents testify to an increasing pharmaceutical interest in this target. This article highlights and reviews research advances published in the patent literature between the first patent publication in June 2002 and November 2006. The article is supplemented with selected publications from the scientific literature, emphasising the possible involvement of PDE10A inhibitors in the treatment of schizophrenia and referring to studies aimed at understanding their mechanism and pathophysiology.

Chemical synthesis and biological evaluation of novel epothilone B and trans-12,13-cyclopropyl epothilone B analogues

Abstract In addition to the total synthesis of the thiomethyl thiazole side chain analogue of epothilone B ( 3 ), a series of related trans -12,13-cyclopropyl epothilone B analogues ( 6 , 8 , 10 , 12 – 14 ) was accomplished. While the synthesis of the epothilone B analogue ( 3 ) proceeded through a Stille coupling of a vinyl iodide substrate containing the epothilone macrocycle with the appropriate side chain stannane, that of the cyclopropyl analogues ( 6 , 8 , 10 , 12 – 14 ) involved a convergent strategy in which a Nozaki–Hiyama–Kishi coupling as a means of introducing the side chains prior to Yamaguchi macrolactonization and final elaboration to the target molecules. The synthesized analogues were subjected to biological evaluation involving in vitro tubulin polymerization, affinity for the microtubule Taxol ® binding site and cell cytotoxicity assays. The results identified the methylthio thiazole side chain as a potency enhancing moiety for the epothilones and shed further light on the structure–activity relationships within this important class of chemotherapeutic agents.

A Multistep Continuous-Flow System for Rapid On-Demand Synthesis of Receptor Ligands

A multistep continuous-flow system for synthesis of receptor ligands by assembly of three variable building blocks in a single unbroken flow is described. The sequence consists of three reactions and two scavenger steps, where a Cbz-protected diamine is reacted with an isocyanate, deprotected, and reacted further with an alkylating agent.

Recent developments in the chemistry, biology andmedicine of the epothilones

The epothilones have occupied center stage on the scenes of total synthesis, chemical biology and medicine for the last five years, no doubt because of their intriguing mode of action and unusually high potency against tumor cells, including multidrug-resistant cell lines. This article highlights the most recent advances within this exciting field. Thus, an overview of recent synthetic endeavors culminating in a new generation of total syntheses and analogues, some with higher potencies than the naturally occurring substances, will be given, and the chemical biology, in particular the current understanding of structure-activity relationships of the epothilones, will also be discussed in light of the latest biological results. In addition, the recently elucidated biosynthetic machinery of the natural epothilone-producing myxobacterium Sorangium cellulosum, as it is now understood, will be described. Finally, some preclinical and clinical studies will be summarized.

Triazoloquinazolines as a novel class of phosphodiesterase 10A (PDE10A) inhibitors.

Novel triazoloquinazolines have been found as phosphodiesterase 10A (PDE10A) inhibitors. Structure-activity studies improved the initial micromolar potency which was found in the lead compound by a 100-fold identifying 5-(1H-benzoimidazol-2-ylmethylsulfanyl)-2-methyl-[1,2,4]triazolo[1,5-c]quinazoline, 42 (PDE10A IC(50)=12 nM) as the most potent compound from the series. Two X-ray structures revealed novel binding modes to the catalytic site of the PDE10A enzyme.

Synthesis and Biological Evaluation of 12,13‐Cyclopropyl and 12,13‐Cyclobutyl Epothilones

With some members in clinical trials, the epothilones command attention as potential anticancer agents of considerable promise. In addition to several naturally occurring substances, an impressive array of epothilone analogues has been constructed and biologically evaluated. 2] We have previously reported the apartialo construction of two 12,13-cyclopropyl epothilone A analogues. Their structures recently came under closer scrutiny by us and by a Bristol ± Myers Squibb (BMS) group, whose independent synthesis of one of these compounds led to a revision of its structure. Here we wish to report i) an unambiguous chemical synthesis of cis-(12S,13S)-cyclopropyl epothilone A (2) and its 15R epimer 3 ; ii) the correct structure of the previously synthesized cyclopropyl epothilones and a mechanistic rationale for their unexpected formation; iii) the chemical synthesis of cis-(12S,13S)-cyclobutyl epothilone A (4) and its 15R epimer 5 ; and iv) the molecular modeling and biological evaluation of the newly synthesized compounds. Remarkably, compounds 2 and 4 exhibit potencies comparable

Discovery of a potent and brain penetrant mGluR5 positive allosteric modulator.

This Letter describes the discovery of a novel series of mGluR5 positive allosteric modulators (PAMs). The lead compound, 11c, exhibits excellent potency (EC(50)=30 nM) in vitro, and reaches high brain levels in both rats and mice after oral administration.

Endogenous 2-oxoglutarate levels impact potencies of competitive HIF prolyl hydroxylase inhibitors

The stability and transcriptional activity of the hypoxia-inducible factors (HIFs) are regulated by oxygen-dependent hydroxylation that is catalyzed by three HIF prolyl 4-hydroxylases (HPHs). Use of HPH inhibition as a mean for HIF-upregulation has recently gained interest as a potential treatment paradigm against neurodegenerative diseases like ischemia and Parkinsons disease. In the present investigation we report the development of a new and robust assay to measure HPH activity. The assay is based on capture of hydroxylated peptide product by the von Hippel-Lindau protein which is directly measured in a scintillation proximity assay. In addition we describe the determination of HPH subtype potencies of HPH inhibitors which either directly or indirectly inhibit the HPH enzyme. The potencies of the HPH inhibitors displayed almost identical IC(50) values toward the HPH1 and HPH2 subtype while the potency against the HPH3 subtype was increased for several of the compounds. For the most potent compound, a hydroxyl thiazole derivative, the potency against HPH2 and HPH3 was 7nM and 0.49nM, respectively corresponding to a 14-fold difference. These results suggest that HPH subtype-selective compounds may be developed. In addition we determined the 2-oxoglutarate concentration in brain tissue and neuronal cell lines as 2-oxoglutarate is an important co-factor used by the HPH enzyme during the hydroxylation reaction. The high intracellular 2-oxoglutarate concentration provides an explanation for the diminished cellular HIF activating potency of a competitive HPH inhibitor compared to its orders of magnitude higher HPH inhibiting potency. The present reported data suggest that in the development of specific Hif prolyl hydroxylase inhibitors the high 2-oxoglutarate tissue level should be taken into account as this might affect the cellular potency. Thus to specifically inhibit the intracellular HPH enzymatic reaction a competitive inhibitor with a low Ki should be developed.

Efficacy switching SAR of mGluR5 allosteric modulators: highly potent positive and negative modulators from one chemotype.

A series of metabotropic glutamate 5 receptor (mGluR5) allosteric ligands with positive, negative or no modulatory efficacy is described. The ability of this series to yield both mGluR5 PAMs and NAMs with single-digit nanomolar potency is unusual, and the underlying SAR is detailed.

Continuous Flow Nucleophilic Aromatic Substitution with Dimethylamine Generated in Situ by Decomposition of DMF

A safe, practical, and scalable continuous flow protocol for the in situ generation of dimethylamine from DMF followed by nucleophilic aromatic substitution of a broad range of aromatic and heteroaromatic halides is reported.