Design, Synthesis, and Biological Characterization of Inhaled p38α/ß MAPK Inhibitors for the Treatment of Lung Inflammatory Diseases.

The identification of novel inhaled p38α/ß mitogen-activated protein kinases (MAPK) (MAPK14/11) inhibitors suitable for the treatment of pulmonary inflammatory conditions has been described. A rational drug design approach started from the identification of a novel tetrahydronaphthalene series, characterized by nanomolar inhibition of p38α with selectivity over p38γ and p38δ isoforms. SAR optimization of 1c is outlined, where improvements in potency against p38α and ligand-enzyme dissociation kinetics led to several compounds showing pronounced anti-inflammatory effects in vitro (inhibition of TNFα release). Targeting of the defined physicochemical properties allowed the identification of compounds 3h, 4e, and 4f, which showed, upon intratracheal instillation, low plasma levels, prolonged lung retention, and anti-inflammatory effects in a rat acute model of a bacterial endotoxin-induced pulmonary inflammation. Compound 4e, in particular, displayed remarkable efficacy and duration of action and was selected for progression in disease models of asthma and chronic obstructive pulmonary disease (COPD).

Conformational Sampling of Macrocyclic Drugs in Different Environments: Can We Find the Relevant Conformations?

Conformational flexibility is a major determinant of the properties of macrocycles and other drugs in beyond rule of 5 (bRo5) space. Prediction of conformations is essential for design of drugs in this space, and we have evaluated three tools for conformational sampling of a set of 10 bRo5 drugs and clinical candidates in polar and apolar environments. The distance-geometry based OMEGA was found to yield ensembles spanning larger structure and property spaces than the ensembles obtained by MOE-LowModeMD (MOE) and MacroModel (MC). Both MC and OMEGA but not MOE generated different ensembles for polar and apolar environments. All three conformational search methods generated conformers similar to the crystal structure conformers for 9 of the 10 compounds, with OMEGA performing somewhat better than MOE and MC. MOE and OMEGA found all six conformers of roxithromycin that were identified by NMR in aqueous solutions, whereas only OMEGA sampled the three conformers observed in chloroform. We suggest that characterization of conformers using molecular descriptors, e.g., the radius of gyration and polar surface area, is preferred to energy- or root-mean-square deviation-based methods for selection of biologically relevant conformers in drug discovery in bRo5 space.

Discovery of AZD3199, An Inhaled Ultralong Acting ß2 Receptor Agonist with Rapid Onset of Action.

A series of dibasic des-hydroxy ß2 receptor agonists has been prepared and evaluated for potential as inhaled ultralong acting bronchodilators. Determination of activities at the human ß-adrenoreceptors demonstrated a series of highly potent and selective ß2 receptor agonists that were progressed to further study in a guinea pig histamine-induced bronchoconstriction model. Following further assessment by onset studies in guinea pig tracheal rings and human bronchial rings contracted with methacholine (guinea pigs) or carbachol (humans), duration of action studies in guinea pigs after intratracheal (i.t.) administration and further selectivity and safety profiling AZD3199 was shown to have an excellent over all profile and was progressed into clinical evaluation as a new ultralong acting inhaled ß2 receptor agonist with rapid onset of action.

Discovery and evolution of phenoxypiperidine hydroxyamide dual CCR3/H1 antagonists. Part I.

The discovery of potent small molecule dual antagonists of the human CCR3 and H(1) receptors is described for the treatment of allergic diseases, for example, asthma and allergic rhinitis. Optimizing in vitro potency and metabolic stability, starting from a CCR1 lead compound, led to compound 20 with potent dual CCR3/H(1) activity and in vitro metabolic stability.

Discovery and evolution of phenoxypiperidine hydroxyamide dual CCR3/H1 antagonists. Part II: optimising in vivo clearance.

The second part of this communication focuses on the resolution of issues surrounding the series of hydroxyamide phenoxypiperidine CCR3/H(1) dual antagonists described in Part I. This involved further structural exploration directed at reducing metabolism and leading to the identification of compound 60 with a greatly improved in vivo pharmacokinetic profile.

Organocatalytic enantioselective one-pot four-component ugi-type multicomponent reaction for the synthesis of epoxy-tetrahydropyrrolo[3,4-b]pyridin-5-ones.

Enantioselective multicomponent reaction: in the presence of a catalytic amount of chiral BINOL-derived phosphoric acid (TRIP), the reaction of an α-isocyanoacetate 1, an aldehyde 2, and an aniline 3, followed by addition of a toluene solution of α,ß-unsaturated acyl chloride 4 afforded the oxa-bridged tricycle 5 in excellent yield, diastereoselectivity, and enantioselectivity. Six chemical bonds, five stereogenic centers, and three cycles were formed in this one-pot four-component reaction.

From libraries to candidate: the discovery of new ultra long-acting dibasic ß2-adrenoceptor agonists.

Libraries of dibasic compounds designed around the molecular scaffold of the DA(2)/ß(2) dual agonist sibenadet (Viozan™) have yielded a number of promising starting points that have been further optimised into novel potent and selective target molecules with required pharmacokinetic properties. From a shortlist, 31 was discovered as a novel, high potency, and highly efficacious ß(2)-agonist with high selectivity and a duration of action commensurable with once daily dosing.

Strategies to improve in vivo toxicology outcomes for basic candidate drug molecules.

A valid PLS-DA model to predict attrition in pre-clinical toxicology for basic oral candidate drugs was built. A combination of aromatic/aliphatic balance, flatness, charge distribution and size descriptors helped predict the successful progression of compounds through a wide range of toxicity testing. Eighty percent of an independent test set of marketed post-2000 basic drugs could be successfully classified using the model, indicating useful forward predictivity. The themes within this work provide additional guidance for medicinal design chemists and complement other literature property guidelines.

Design-driven LO: the discovery of new ultra long acting dibasic ß2-adrenoceptor agonists.

Starting with the molecular scaffold of the DA(2)/ß(2) dual agonist sibenadet (Viozan™), a number of molecular changes were incorporated, which were designed to increase the potency and selectivity of the target molecule, and improve its pharmacokinetics. Through this process a novel, high potency, full ß(2)-agonist with high selectivity and long duration capable of being dosed once daily has been discovered.

Design driven HtL: The discovery and synthesis of new high efficacy ß2-agonists.

The design and synthesis of a new series of high efficacy ß(2)-agonists devoid of the key benzylic alcohol present in previously described highly efficacious ß(2)-agonists is reported. A hypothesis for the unprecedented level of efficacy is proposed based on considerations of ß(2)-adrenoceptor crystal structure, other biophysical data and modeling studies.

The discovery of new spirocyclic muscarinic M3 antagonists.

The optimisation of a new series of high potency muscarinic M3 antagonists, derived from high throughput screening library hit is described.

Molybdenum-mediated carbonylation of aryl halides with nucleophiles using microwave irradiation.

A new, efficient, and practical molybdenum-mediated carbonylation of aryl and heteroaryl halides with a variety of nucleophiles is described using microwave irradiation. A range of reactions illustrating the wide scope of this chemistry were carried out and proceeded in good to excellent yields.

Novel aryl and heteroaryl acyl sulfamide synthesis via microwave-assisted palladium-catalyzed carbonylation.

A novel, simple synthesis of aryl and heteroaryl acyl sulfamides has been developed via palladium-catalyzed carbonylation of aryl or heteroaryl halides in the presence of sulfamide nucleophiles. A range of reactions illustrating the wide scope of this reaction was carried out under microwave irradiation in a vessel equipped with a gas inlet adapter and proceeded in good to excellent yields.

Muscarinic antagonist-beta-adrenergic agonist dual pharmacology molecules as bronchodilators: a patent review.

BACKGROUND: The proven efficacy of several anti-cholinergics and beta(2)-agonists and their combinations in both chronic obstructive pulmonary disease (COPD) and asthma strongly validates this therapeutic approach. As a consequence and although technically challenging, over the past 4 years there has been a growing interest in the generation of dual pharmacology Muscarinic-receptor antagonists-beta(2)-adrenergic receptor agonists (MABAs) for the treatment of COPD. OBJECTIVE/METHODS: This article surveys and reviews the research activity in the MABA area to the end of August 2008. RESULTS/CONCLUSION: Although the activity in this field seems to still be limited to a few companies, significant progress in the discovery of a MABA has been achieved with the progression of at least one candidate (GSK-961081) to the clinic.

Synthesis of four novel natural product inspired scaffolds for drug discovery.

Inspired by the novel spiro structures of a number of bioactive natural products such as the histrionicotoxins, a series of novel spiro scaffolds have been designed and robust syntheses developed. The scaffolds are ready-to-use building blocks and can be easily prepared on a 5-20 g scale. They contain two amino groups (one Boc-protected) and have been designed for ease of conversion to a lead generation library, using either amide formation or reductive amination procedures. The synthesis of the 1,9-diazaspiro[5.5]undecane and 3,7-diazaspiro[5.6]dodecane ring systems was achieved using RCM as the key step. A simple workup procedure is reported for the removal of highly colored ruthenium residues. The synthesis of the 1,8-diazaspiro[4.5]decane scaffold has been achieved using a bromine-mediated 5-endo cyclization of the corresponding 4-aminobutene intermediate under acidic conditions. This is the first example of this type of cyclization to be reported. A novel mechanism involving a bromine transfer reaction from an initially formed bromonium ion to a neighboring nitrogen atom is suggested as the reason for the failure of this type of reaction under "normal" bromination conditions. An unusual rearrangement of a 1-acyl-1,9-diazaspiro[5.5]undecane to the corresponding 9-acyl-1,9-diazaspiro[5.5]undecane is reported.

Discovery of potent and selective adamantane-based small-molecule P2X(7) receptor antagonists/interleukin-1beta inhibitors.

A novel series of antagonists of the human P2X7 receptor is described. Modification of substituents enabled identification of compounds selective for the rat P2X7 receptor and provides useful pharmacological tools for evaluation of the role of P2X7 in disease.

Solution structures of thiopeptide antibiotics.

A detailed NMR study of the thiopeptide amythiamicin D establishes its solution conformation and the presence of a single intramolecular hydrogen bond involving NH13 and O28, and also provides the first evidence for self-association of thiopeptides in solution.

Total synthesis of the thiopeptide antibiotic amythiamicin D.

The thiopeptide (or thiostrepton) antibiotics are a class of sulfur containing highly modified cyclic peptides with interesting biological properties, including reported activity against MRSA and malaria. Described herein is the total synthesis of the thiopeptide natural product amythiamicin D, which utilizes a biosynthesis-inspired hetero-Diels-Alder route to the pyridine core of the antibiotic as a key step. Preliminary studies using a range of serine-derived 1-ethoxy-2-azadienes established that hetero-Diels-Alder reaction with N-acetylenamines proceeded efficiently under microwave irradiation to give 2,3,6-trisubstituted pyridines. The thiazole building blocks of the antibiotic were obtained by either classical Hantzsch reactions or by dirhodium(II)-catalyzed chemoselective carbene N-H insertion followed by thionation, and were combined to give the bis-thiazole that forms the left-hand fragment of the antibiotic. The key Diels-Alder reaction of a tris-thiazolyl azadiene with benzyl 2-(1-acetylaminoethenyl)thiazole-4-carboxylate gave the core tetrathiazolyl pyridine, which was elaborated into the natural product by successive incorporation of glycine and bis-thiazole fragments followed by macrocyclization.

Novel enantioselective synthesis of 1,3-butadien-2-ylmethanols via tandem alkylbromide-epoxide vinylations using dimethylsulfonium methylide.

[reaction: see text] The treatment of chiral trans-disubstituted and trisubstituted 2,3-epoxy-1-bromides with an excess of dimethylsulfonium methylide 1 affords the corresponding 1,3-butadien-2-ylmethanols in good to excellent yields via a double one-carbon homologation.