Substituted indole-1-acetic acids as potent and selective CRTh2 antagonists-discovery of AZD1981.

Novel indole-3-thio-, 3-sulfonyl- and 3-oxy-aryl-1-acetic acids are reported which are potent, selective antagonists of the chemoattractant receptor-homologous expressed on Th2 lymphocytes receptor (CRTh2 or DP2). Optimization required maintenance of high CRTh2 potency whilst achieving a concomitant reduction in rates of metabolism, removal of cyp p450 inhibition and minimization of aldose reductase and aldehyde reductase activity. High quality compounds suitable for in vivo studies are highlighted, culminating in the discovery of AZD1981 (22).

Development of isotope-enriched phosphatidylinositol-4- and 5-phosphate cellular mass spectrometry probes.

Synthetic phosphatidylinositol phosphate (PtdInsP n ) derivatives play a pivotal role in broadening our understanding of PtdInsP n metabolism. However, the development of such tools is reliant on efficient enantioselective and regioselective synthetic strategies. Here we report the development of a divergent synthetic route applicable to the synthesis of deuterated PtdIns4P and PtdIns5P derivatives. The synthetic strategy developed involves a key enzymatic desymmetrisation step using Lipozyme TL-IM®. In addition, we optimised the large-scale synthesis of deuterated myo-inositol, allowing for the preparation of a series of saturated and unsaturated deuterated PtdIns4P and PtdIns5P derivatives. Experiments in MCF7 cells demonstrated that these deuterated probes enable quantification of the corresponding endogenous phospholipids in a cellular setting. Overall, these deuterated probes will be powerful tools to help improve our understanding of the role played by PtdInsP n in physiology and disease.

Discovery of small molecule human C5a receptor antagonists.

A novel series of small molecule C5a antagonists is reported. In particular, in vitro metabolic studies and solution based combinatorial synthesis are demonstrated as useful tools for the rapid identification of antagonists with low in vitro clearance. Members of this series specifically inhibited the binding of (125)I-labeled C5a to human recombinant C5a receptor (C5aR). In functional cell assays these compounds displayed surmountable antagonism against C5a and did not demonstrate any detectable agonist activity.

Identification and Pharmacological Profile of an Indane Based Series of Ghrelin Receptor Full Agonists.

Cachexia and muscle wasting are very common among patients suffering from cancer, chronic obstructive pulmonary disease, and other chronic diseases. Ghrelin stimulates growth hormone secretion via the ghrelin receptor, which subsequently leads to increase of IGF-1 plasma levels. The activation of the GH/IGF-1 axis leads to an increase of muscle mass and functional capacity. Ghrelin further acts on inflammation, appetite, and adipogenesis and for this reason was considered an important target to address catabolic conditions. We report the synthesis and properties of an indane based series of ghrelin receptor full agonists; they have been shown to generate a sustained increase of IGF-1 levels in dog and have been thoroughly investigated with respect to their functional activity.

Pioneering government-sponsored drug repositioning collaborations: progress and learning.

A new model for translational research and drug repositioning has recently been established based on three-way partnerships between public funders, the pharmaceutical industry and academic investigators. Through two pioneering initiatives - one involving the Medical Research Council in the United Kingdom and one involving the National Center for Advancing Translational Sciences of the National Institutes of Health in the United States - new investigations of highly characterized investigational compounds have been funded and are leading to the exploration of known mechanisms in new disease areas. This model has been extended beyond these first two initiatives. Here, we discuss the progress to date and the unique requirements and challenges for this model.

One-Pot Asymmetric Nitro-Mannich/Hydroamination Cascades for the Synthesis of Pyrrolidine Derivatives: Combining Organocatalysis and Gold Catalysis.

The highly enantioselective preparation of trisubstituted pyrrolidine derivatives employing a one-pot nitro-Mannich/hydroamination cascade is reported. This cascade approach utilizes an asymmetric bifunctional organocatalytic nitro-Mannich reaction followed by a gold-catalyzed allene hydroamination reaction. The products are afforded in good yields and excellent diastereo- and enantioselectivities.

Potent dual inhibitors of TORC1 and TORC2 complexes (KU-0063794 and KU-0068650) demonstrate in vitro and ex vivo anti-keloid scar activity.

Mammalian target of rapamycin (mTOR) is essential in controlling several cellular functions. This pathway is dysregulated in keloid disease (KD). KD is a common fibroproliferative dermal lesion with an ill-defined treatment strategy. KD demonstrates excessive matrix deposition, angiogenesis, and inflammatory cell infiltration. In KD, both total and phosphorylated forms of mTOR and p70(S6K)(Thr421/Ser424) are upregulated. Therefore, the aim of this study was to investigate adenosine triphosphate-competitive inhibitors of mTOR kinase previously unreported in keloid and their comparative efficacy with Rapamycin. Here, we present two mTOR kinase inhibitors, KU-0063794 and KU-0068650, that target both mTORC1 and mTORC2 signaling. Treatment with either KU-0063794 or KU-0068650 resulted in complete suppression of Akt, mTORC1, and mTORC2, and inhibition of keloid cell spreading, proliferation, migration, and invasive properties at a very low concentration (2.5 µmol l(-1)). Both KU-0063794 and KU-0068650 significantly (P<0.05) inhibited cell cycle regulation and HIF1-α expression compared with that achieved with Rapamycin alone. In addition, both compounds induced shrinkage and growth arrest in KD, associated with the inhibition of angiogenesis, induction of apoptosis, and reduction in keloid phenotype-associated markers. In contrast, Rapamycin induced minimal antitumor activity. In conclusion, potent dual mTORC1 and mTORC2 inhibitors display therapeutic potential for the treatment of KD.

Diastereoselective synthesis of pyrrolidine derivatives via a one-pot nitro-Mannich/hydroamination cascade using base and gold catalysis.

An efficient one-pot nitro-Mannich/hydroamination cascade reaction for the synthesis of substituted pyrrolidines bearing three stereocentres is reported. Proceeding under the control of a combination of base and gold(I) catalysts, the cascade reaction affords the pyrrolidine products in high yields with good to excellent diastereoselectivities.

Activation of the Wnt pathway through AR79, a GSK3ß inhibitor, promotes prostate cancer growth in soft tissue and bone.

UNLABELLED: Due to its bone anabolic activity, methods to increase Wnt activity, such as inhibitors of dickkopf-1 and sclerostin, are being clinically explored. Glycogen synthase kinase (GSK3ß) inhibits Wnt signaling by inducing ß-catenin degradation, and a GSK3ß inhibitor, AR79, is being evaluated as an osteoanabolic agent. However, Wnt activation has the potential to promote tumor growth; therefore, the goal of this study was to determine if AR79 has an impact on the progression of prostate cancer. Prostate cancer tumors were established in subcutaneous and bone sites of mice followed by AR79 administration, and tumor growth, ß-catenin activation, proliferation, and apoptosis were assessed. Additionally, prostate cancer and osteoblast cell lines were treated with AR79, and ß-catenin status, proliferation (with ß-catenin knockdown in some cases), and proportion of ALDH(+)CD133(+) stem-like cells were determined. AR79 promoted prostate cancer tumor growth, decreased phospho-ß-catenin, increased total and nuclear ß-catenin, and increased tumor-induced bone remodeling. Additionally, AR79 treatment decreased caspase-3 and increased Ki67 expression in tumors and increased bone formation in normal mouse tibiae. Similarly, AR79 inhibited ß-catenin phosphorylation, increased nuclear ß-catenin accumulation in prostate cancer and osteoblast cell lines, and increased proliferation of prostate cancer cells in vitro through ß-catenin. Furthermore, AR79 increased the ALDH(+)CD133(+) cancer stem cell-like proportion of the prostate cancer cell lines. In conclusion, AR79, while being bone anabolic, promotes prostate cancer cell growth through Wnt pathway activation. IMPLICATIONS: These data suggest that clinical application of pharmaceuticals that promote Wnt pathway activation should be used with caution as they may enhance tumor growth.

One-pot catalytic enantioselective synthesis of tetrahydropyridines via a nitro-Mannich/hydroamination cascade.

The highly enantioselective preparation of synthetically useful tetrahydropyridine derivatives employing a one-pot nitro-Mannich/hydroamination cascade is reported. This approach utilizes an asymmetric organocatalytic nitro-Mannich reaction followed by a gold-catalyzed alkyne hydroamination/isomerization sequence that yields the desired tetrahydropyridines in good yields and high diastereo- and enantioselectivities.

SuperQuat N-acyl-5,5-dimethyloxazolidin-2-ones for the asymmetric synthesis of alpha-alkyl and beta-alkyl aldehydes.

The proclivity of alpha-branched N-2'-benzyl-3'-phenylpropionyl derivatives of (S)-4-benzyl-5,5-dimethyl-, (S)-4-phenyl-5,5-dimethyl-, (S)-4-isopropyl-5,5-dimethyl-, (S)-4-benzyl- and (S)-4-benzyl-5,5-diphenyl-oxazolidin-2-ones to generate directly 2-benzyl-3-phenylpropionaldehyde upon hydride reduction with DIBAL is investigated. The (S)-4-benzyl-5,5-dimethyl-derivative proved optimal for inhibition of endocyclic nucleophilic attack, giving 2-benzyl-3-phenylpropionaldehyde in good yield upon reduction. Application of this methodology for the asymmetric synthesis of chiral aldehydes via diastereoselective enolate alkylation of a range of (S)-N-acyl-4-benzyl-5,5-dimethyloxazolidin-2-ones to afford and array of alpha-substituted-N-acyl-5,5-dimethyloxazolidin- 2-ones (85-94% de) and subsequent reduction with DIBAL afforded directly non-racemic alpha-substituted aldehydes without loss of stereochemical integrity (87-94% ee). The extension of this protocol for the asymmetric synthesis of beta-substituted aldehydes is demonstrated, via the diastereoselective conjugate addition of a range of organocuprates to (S)-N-acyl-4-phenyl-5,5-dimethyloxazolidin-2-ones which proceeds with high diastereoselectivity (generally > 95% de). Reduction of the conjugate addition products with DIBAL gives non-racemic beta-substituted aldehydes in high yields and in high ee (generally > 95% ee). This methodology is exemplified by the asymmetric synthesis of (R)-3-isopropenylhept-6-enal, which has previously been used in the synthesis of (3Z,6R)-3-methyl-6-isopropenyl-3,9-decadien-1-yl acetate, a component of the sex pheromones of the California red scale.

N-acyl-5,5-dimethyloxazolidin-2-ones as latent aldehyde equivalents.

A study of the properties of N-hydrocinnamoyl- derivatives of 5,5-dimethyloxazolidin-2-one, 4,4-dimethyloxazolidin-2-one and oxazolidin-2-one upon hydride reduction with DIBAL-H demonstrates that the 5,5-dimethyl-group is essential for inhibition of endocyclic nucleophilic attack. For instance, treatment of N-hydrocinnamoyl-5,5-dimethyloxazolidin-2-one with DIBAL-H results in the selective formation of the stable N-1'-hydroxyalkyl derivative which may be regarded as a masked hydrocinnamaldehyde equivalent, as treatment under basic conditions affords the parent aldehyde in excellent yield. Treatment of N-hydrocinnamoyl-4,4-dimethyloxazolidin-2-one with DIBAL-H under identical conditions affords a complex mixture of products, including the formate ester product of endocyclic cleavage. As an alternate strategy, DIBAL-H reduction of straight chain and branched N-acyl-5,5-dimethyloxazolidin-2-one derivatives, followed by a Horner-Wadsworth-Emmons reaction affords alpha,beta-unsaturated esters in good yields. Branching alpha- to the exocyclic carbonyl in N-acyl-oxazolidinones inhibits DIBAL-H reduction, but this can be overcome by precomplexation with ZnCl2, with subsequent fragmentation generating either the corresponding aldehyde or alpha,beta-unsaturated esters. The addition of ZnCl2 has been shown to increase the diastereoselectivity observed in Wadsworth-Horner-Emmons reactions of lithiated phosphonates.