Andrew Mather

Iridium-catalysed labelling of anilines, benzylamines and nitrogen heterocycles using deuterium gas and cycloocta-1,5-dienyliridium(I) 1,1,1,5,5,5-hexafluoropentane-2,4-dionate

A wide range of variously substituted anilines, benzylamines, and nitrogen heterocycles may be conveniently deuterated by exchange with deuterium gas and cycloocta-1,5-dienyliridium(I) 1,1,1,5,5,5-hexafluoropentane-2,4-dionate. The isotopic exchange can be carried out efficiently in dimethylformamide or dimethylacetamide, hence it is directly applicable to the deuteration of polar compounds such as pharmaceuticals. Isotope incorporation is rapid and yields ortho-regiospecificity.

Parallel chemistry investigations of ortho-directed hydrogen isotope exchange between substituted aromatics and isotopic water: novel catalysis by cyclooctadienyliridium(I)pentan-1,3-dionates

Abstract Novel iridium-based catalysts which promote ortho -directed hydrogen isotope exchange between substituted aromatics and isotopic water have been identified via a combination of screening and subsequent ligand optimisation. The catalysts are more active, operate at lower temperature and are applicable to a wider variety of substrates than previously known systems.

Cathepsin C Inhibitors: Property Optimization and Identification of a Clinical Candidate

A lead generation and optimization program delivered the highly selective and potent CatC inhibitor 10 as an in vivo tool compound and potential development candidate. Structural studies were undertaken to generate SAR understanding.

The design of a novel series of muscarinic receptor antagonists leading to AZD8683, a potential inhaled treatment for COPD.

A novel series of muscarinic receptor antagonists was developed, with the aim of identifying a compound with high M3 receptor potency and a reduced risk of dose-limiting side effects with potential for the treatment of COPD. Initial compound modifications led to a novel cycloheptyl series, which was improved by focusing on a quinuclidine sub-series. A wide range of N-substituents was evaluated to determine the optimal substituent providing a high M3 receptor potency, high intrinsic clearance and high human plasma protein binding. Compounds achieving in vitro study criteria were selected for in vivo evaluation. Pharmacokinetic half-lives, inhibition of bronchoconstriction and duration of action, as well as systemic side effects, induced by the compounds were assessed in guinea-pig models. Compounds with a long duration of action and good therapeutic index were identified and AZD8683 was selected for progression to the clinic.

Preparation of remacemide hydrochloride labelled with carbon‐14, carbon‐13, deuterium and tritium

The anti-epileptic agent remacemide hydrochloride has been prepared labelled with 14C, from [carbonyl-14C]acetophenone, and with 13C from [13C6]benzene, [1,2-13C]acetyl chloride and [1-13C]glycine. [2-3H]Glycine was utilised to prepare remacemide labelled with tritium at low specific activity. In addition other 2H- and high specific activity 3H-isotopomers of the drug, and of an active metabolite of the drug, were prepared by hydrogen isotope exchange methodology. The R-12C/S-14C and S-12C/R-14C pseudoracemic drugs were also prepared by a synthesis involving resolution of a 14C-labelled amine intermediate via fractional crystallisation of the dibenzoyltartrate salts. Copyright

A RIA combined with spe for the determination of a dual D2-receptor and β2-adrenoceptor agonist, AR-C68397XX, in human plasma

A radioimmunoassay has been developed for the determination of AR-C68397XX, a dual D2-receptor and beta2-adrenoceptor agonist, in human plasma. The method incorporates solid phase sample extraction and is suitable for the determination of the analyte at pg ml(-1) concentrations. The antiserum was raised in Suffolk cross sheep following primary and booster immunisations with an immunogen prepared by conjugating a carboxyphenylmethyl derivative of AR-C68397XX, to bovine serum albumin. The radioligand was prepared by the 125I-labelled iodination of a derivative of AR-C68397XX. The solid phase extraction procedure, using octadecyl sorbent, was introduced to remove matrix interferences in the plasma and to enhance method sensitivity. The calibration range is 20-500 pg ml(-1), using 0.5 ml of undiluted human plasma sample.