Identification of a new series of non-peptidic NK3 receptor antagonists.

The identification and structure-activity relationships of 2-aminomethyl-1-aryl cyclopropane carboxamides as novel NK(3) receptor antagonists are reported. The compound series was optimized to give analogues with low nanomolar binding to the NK(3) receptor and brain exposure, leading to activity in vivo in the senktide-induced hypoactivity model in gerbils.

Novel NK(3) receptor antagonists for the treatment of schizophrenia and other CNS indications.

The cloning of the three tachykinin receptors in the late 1980s formed the basis of intense preclinical research efforts into the systems relating to the tachykinin receptors, as well as compound screening campaigns. Remarkably, orally active non-peptide antagonists were successfully identified for all three of the tachykinin receptors, providing tools for further evaluation of the pharmacology of these receptor systems. The NK3 receptor (mammalian tachykinin receptor 3), which exhibited a discrete expression pattern and the modulatory regulation of various transmitter systems in the CNS, has attracted significant interest. Preclinical studies demonstrated that the NK3 receptor might be a promising target for CNS disorders, and clinical trials with non-peptide NK3 receptor antagonists have been performed for indications such as schizophrenia, major depressive disorder, panic attacks and Parkinson's disease. In particular, the positive results of the schizophrenia meta-trial with osanetant increased the focus on the NK3 receptor system and its clinical potential. Consequently, a significant number of patents covering non-peptide antagonists for the NK3 receptor have been published during the past decade. This review describes the most recent NK3 receptor antagonists (published from 2004 to 2009), which are classified into seven unique templates.

Syntheses of novel myxopyronin B analogs as potential inhibitors of bacterial RNA polymerase.

Based upon observations from our initial findings, additional myxopyronin B analogs have been prepared and tested for in vitro inhibitory activity against DNA-dependent RNA polymerase and antibacterial activity against Escherichia coli and Staphylococcus aureus.

Structure-guided discovery of novel aminoglycoside mimetics as antibacterial translation inhibitors.

We report the structure-guided discovery, synthesis, and initial characterization of 3,5-diamino-piperidinyl triazines (DAPT), a novel translation inhibitor class that targets bacterial rRNA and exhibits broad-spectrum antibacterial activity. DAPT compounds were designed as structural mimetics of aminoglycoside antibiotics which bind to the bacterial ribosomal decoding site and thereby interfere with translational fidelity. We found that DAPT compounds bind to oligonucleotide models of decoding-site RNA, inhibit translation in vitro, and induce translation misincorporation in vivo, in agreement with a mechanism of action at the ribosomal decoding site. The novel DAPT antibacterials inhibit growth of gram-positive and gram-negative bacteria, including the respiratory pathogen Pseudomonas aeruginosa, and display low toxicity to human cell lines. In a mouse protection model, an advanced DAPT compound demonstrated efficacy against an Escherichia coli infection at a 50% protective dose of 2.4 mg/kg of body weight by single-dose intravenous administration.

Synthesis of dehydroalanine fragments as thiostrepton side chain mimetics.

Syntheses of dehydroalanine derivatives via a solid-support route, starting from selenocystein, and via conventional solution phase chemistry are described along with initial biological testing. The target compounds were designed as mimetics of the dehydroalanine side chain of the macrocyclic antibiotic thiostrepton that acts on the bacterial ribosome.

Myxopyronin B analogs as inhibitors of RNA polymerase, synthesis and biological evaluation.

A series of myxopyronin B analogs has been prepared via a convergent synthetic route and were tested for in vitro inhibitory activity against DNA-dependent RNA polymerase and antibacterial activity against E. coli and S. aureus. The parent lead compound proved to be very sensitive to even small changes. Only the achiral desmethyl myxopyronin B (1a) provided enhanced potency.

Studies toward diazonamide A: initial synthetic forays directed toward the originally proposed structure.

A brief introduction into the chemistry of diazonamide A (1) is followed by first-generation sequences to access the originally proposed structure for this unusual marine natural product. These explorations identified a route capable of delivering a model compound possessing the complete heteroaromatic core of the natural product, highlighting in the process several unanticipated synthetic challenges which led both to new methodology as well as an improved synthetic plan that was successfully applied to fully functionalized intermediates.

Rational design of azepane-glycoside antibiotics targeting the bacterial ribosome.

RNA recognition by natural aminoglycoside antibiotics depends on the 2-deoxystreptamine (2-DOS) scaffold which participates in specific hydrogen bonds with the ribosomal decoding-site target. Three-dimensional structure information has been used for the design of azepane-monoglycosides, building blocks for novel antibiotics in which 2-DOS is replaced by a heterocyclic scaffold. Azepane-glycosides showed target binding and translation inhibition in the low micromolar range and inhibited growth of Staphylococcus aureus, including aminoglycoside-resistant strains.

Novel paromamine derivatives exploring shallow-groove recognition of ribosomal-decoding-site RNA.

Natural aminoglycoside antibiotics recognize an internal loop of bacterial ribosomal-decoding-site RNA by binding to the deep groove of the RNA structure. We have designed, synthesized, and tested RNA-targeted paromamine derivatives that exploit additional interactions on the shallow groove face of the decoding-site RNA. An in vitro transcription-translation assay of a series of 6'-derivatives showed the 6'-position to be very sensitive to substitution. This result suggests that the group at the 6'-position plays a pivotal role in RNA target recognition.

Novel 2,5-dideoxystreptamine derivatives targeting the ribosomal decoding site RNA.

The ribosomal decoding site is the target of aminoglycoside antibiotics that specifically recognize an internal loop RNA structure. We synthesized RNA-targeted 2,5-dideoxystreptamine-4-amides in which a sugar moiety in natural aminoglycosides is replaced by heterocycles.

A Pyrazole to Furan Rearrangement. Thermolysis of 5-Azido-4-formylpyrazoles.

5-Azido-3-benzyl-4-formyl-1-phenylpyrazoles 1a-c extrude dinitrogen upon heating in toluene to give the corresponding nitrenes, which immediately rearrange via a new ring-opening ring-closure reaction to produce an equimolar mixture of 4-cyano-2-phenyl-3-phenylazofurans 2a-c and 3-benzyl-4-cyano-1-phenylpyrazoles 3a-c. The formation of the 4-cyano-2-phenyl-3-phenylazofurans 2a-c is the first example in the pyrazole series of a nitrene rearrangement, in which the parent heterocyclic system of the product differs from that of the starting material. The isolation of equimolar amounts of the two products points to the fact that their formation occurs by two mechanistically interconnected pathways, between which the exchange of a redox equivalent takes place. Evidence for the existence of two mechanistically interlinked pathways is presented, and the insight into the stoechiometry of the reaction is taken advantage of to optimize the reaction with respect to either of the two products 2 or 3. Thus, it is demonstrated how one can bias the two pathways using external reagents, thereby changing the product distribution ratio 2:3 from 1:1 in the unbiased case, to 1:4 in one direction, and to better than 20:1 in the other direction.

Tetrathiafulvalene Belts with Large Cavities.

The latest member of the cyclophane family, the macrotricyclic tetrathiafulvalene (TTF) "belt", is now available. A general synthetic strategy for the construction of tetraconnected belt-type TTFs (shown schematically) has been developed, made possible by the use of a TTF with two different protecting groups. In the solid-state structure of one of the three TTF-belts prepared two chloroform molecules reside inside the spacious cavity.

Stable Macrocyclic and Tethered Donor-Acceptor Systems. Intramolecular Bipyridinium and Tetrathiafulvalene Assemblies.

A series of compounds has been prepared in which a tetrathiafulvalene (TTF)-derived donor is covalently tethered or bridged to one or more bipyridinium (viologen) acceptors. The relative degree of charge transfer observed in this series is discussed as a function of structure. The greatest CT effect is seen in the cyclophanes 9a-c and 13.