Nicholas Kindon

Hit-to-lead studies: the discovery of potent, orally bioavailable triazolethiol CXCR2 receptor antagonists.

A Hit-to-Lead optimisation programme was carried out on the high throughput screening hit, the triazolethiol 1, resulting in the discovery of the potent, orally bioavailable triazolethiol CXCR2 receptor antagonist 45.

The medicinal chemistry of the P2 receptor family.

Publisher Summary This chapter reviews that the purinoreceptors are a family of receptors that are activated by nucleosides and nucleotides. The purinoreceptors is divided into two families: The P 1 receptors, where nucleosides are more active than nucleotides and the P 2 receptors, where nucleotides are more active than nucleosides. The chapter concentrate on the medicinal chemistry of the P 2 receptor family. It also reviews the P 2 receptor is divided into two major classes, P2X and P2Y. The P2X receptors belong to the ligand-gated cation channel family; whereas the P2Y receptors are members of the seven transmembrane G-protein coupled receptor family. P2X and P2Y receptors are numbered sequentially according to the clone being reported. Capital letters are used to denote functional mammalian receptors or their non-mammalian homologues. Lower case is used to denote orphan mammalian receptors such as receptors having P 2 sequence homology, but no identified functional response and functional non-mammalian receptors with no known mammalian homologue. This system has led to non-sequential numbering of confirmed mammalian P 2 receptors and may necessitate further revision of nomenclature for this class of receptors.

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.

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.

From UTP to AR-C118925, the discovery of a potent non nucleotide antagonist of the P2Y2 receptor

The G protein-coupled P2Y2 receptor, activated by ATP and UTP has been reported as a potential drug target for a wide range of important clinical conditions, such as tumor metastasis, kidney disorders, and in the treatment of inflammatory conditions. However, pharmacological studies on this receptor have been impeded by the limited reported availability of stable, potent and selective P2Y2R antagonists. This article describes the design and synthesis of AR-C118925, a potent and selective non-nucleotide antagonist of the P2Y2 receptor discovered using the endogenous P2Y2R agonist UTP as the chemical starting point.

Design and Elaboration of a Tractable Tricyclic Scaffold To Synthesize Druglike Inhibitors of Dipeptidyl Peptidase-4 (DPP-4), Antagonists of the C–C Chemokine Receptor Type 5 (CCR5), and Highly Potent and Selective Phosphoinositol-3 Kinase δ (PI3Kδ) Inhibitors

A novel molecular scaffold has been synthesized, and its incorporation into new analogues of biologically active molecules across multiple target classes will be discussed. In these studies, we have shown use of the tricyclic scaffold to synthesize potent inhibitors of the serine peptidase DPP-4, antagonists of the CCR5 receptor, and highly potent and selective PI3K δ isoform inhibitors. We also describe the predicted physicochemical properties of the resulting inhibitors and conclude that the tractable molecular scaffold could have potential application in future drug discovery programs.

Discovery of AZD-2098 and AZD-1678, Two Potent and Bioavailable CCR4 Receptor Antagonists

N-(5-Bromo-3-methoxypyrazin-2-yl)-5-chlorothiophene-2-sulfonamide 1 was identified as a hit in a CCR4 receptor antagonist high-throughput screen (HTS) of a subset of the AstraZeneca compound bank. As a hit with a lead-like profile, it was an excellent starting point for a CCR4 receptor antagonist program and enabled the rapid progression through the Lead Identification and Lead Optimization phases resulting in the discovery of two bioavailable CCR4 receptor antagonist candidate drugs.