Lilian Alcaraz

Characterization of a selective and potent antagonist of human P2X7 receptors, AZ11645373

The ATP‐gated P2X7 receptor has been shown to play a role in several inflammatory processes, making it an attractive target for anti‐inflammatory drug discovery. We have recently identified a novel set of cyclic imide compounds that inhibited P2X7 receptor‐mediated dye uptake in human macrophage THP‐1 cells. In this study the actions and selectivity of one of these compounds, AZ11645373, were characterized.

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.

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

Background: The proven efficacy of several anti-cholinergics and β2-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-β2-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.

Biosynthesis inspired Diels–Alder route to pyridines: synthesis of the 2,3-dithiazolylpyridine core of the thiopeptide antibiotics

Reaction of serine derived 1-alkoxy-2-azadienes with dehydroalanine derived dienophiles results in Diels-Alder reaction and aromatisation to give 2,3,6-trisubstituted pyridines, thereby establishing the viability of the proposed biosynthetic route to the pyridine ring of the thiopeptide antibiotics originally proposed by Bycroft and Gowland.

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.

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,β-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.

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.

Design driven HtL: The discovery and synthesis of new high efficacy β2-agonists

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

Design-driven LO: The discovery of new ultra long acting dibasic β2-adrenoceptor agonists

Starting with the molecular scaffold of the DA(2)/β(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 β(2)-agonist with high selectivity and long duration capable of being dosed once daily has been discovered.

From libraries to candidate: The discovery of new ultra long-acting dibasic β2-adrenoceptor agonists

Libraries of dibasic compounds designed around the molecular scaffold of the DA(2)/β(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 β(2)-agonist with high selectivity and a duration of action commensurable with once daily dosing.