Iain Walters

A concise total synthesis of salinosporamide A

A concise and straightforward 14-step total synthesis of (+/-)-salinosporamide A, based on a diastereoselective acid-catalysed intramolecular cyclisation of to the pyrrolidinone , and a regioselective reduction of the malonate derivative 8b to the aldehyde 9, is described.

Identification of the Clinical Candidate (R)-(1-(4-Fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone (CORT125134): A Selective Glucocorticoid Receptor (GR) Antagonist

The nonselective glucocorticoid receptor (GR) antagonist mifepristone has been approved in the U.S. for the treatment of selected patients with Cushings syndrome. While this drug is highly effective, lack of selectivity for GR leads to unwanted side effects in some patients. Optimization of the previously described fused azadecalin series of selective GR antagonists led to the identification of CORT125134, which is currently being evaluated in a phase 2 clinical study in patients with Cushings syndrome.

Library synthesis using solution phase capping of solid phase derived intermediates

Abstract An efficient protocol for the preparation of combinatorial libraries is described. The methodology first deploys solid phase chemistry to synthesize a 96-well array of intermediates linked to resin via a latent reactive functionality such as a benzyl ether, tert-amine or thioether. Cleavage from the resin is accompanied by transformation of the linker to a reactive functionality, namely a benzyl halide, sec-amine or thiol. Aliquots of this array of reactive intermediates are each capped with a different solution phase reactant to deliver the final library in 96-well format, ready for high throughput screening.

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.

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.