Donald Mcleod

Phosphonamidates and phosphonamidate esters as HIV-1 protease inhibitors

Simple dipeptides incorporating phosphonamidate and phosphonamidate ester isosteres for the scissile peptide bond are modest inhibitors of the HIV-1 protease. Their synthesis and inhibition studies are described.

Discovery and characterization of AZD9272 and AZD6538—Two novel mGluR5 negative allosteric modulators selected for clinical development

AZD9272 and AZD6538 are two novel mGluR5 negative allosteric modulators selected for further clinical development. An initial high-throughput screening revealed leads with promising profiles, which were further optimized by minor, yet indispensable, structural modifications to bring forth these drug candidates. Advantageously, both compounds may be synthesized in as little as one step. Both are highly potent and selective for the human as well as the rat mGluR5 where they interact at the same binding site than MPEP. They are orally available, allow for long interval administration due to a high metabolic stability and long half-lives in rats and permeate the blood brain barrier to a high extent. AZD9272 has progressed into phase I clinical studies.

Substrate attenuation : an approach to improve antibody catalysis

Abstract Antibodies raised to quinaldine phosphonamide 1a showed no ability to hydrolyze its most homologous substrates amide and ester 2 and 3, respectively. However, within this same set of antibodies some thirteen showed a great propensity to hydrolyse a structurally similar naphthyl ester. In addition to heteroatom discrimination one of the antibodies examined in detail displayed an increase in catalytic efficiency presumably via weak apparent binding (Km) when phenylesters were employed as substrates. These findings suggest abzyme catalysis may be improved via substrate attenuation. Antibodies raised to quinaldine phosphonamide 1a showed no ability to hydrolyze its most homologous substrates amide and ester 2 and 3, respectively. However, within this same set of antibodies some thirteen showed a great propensity to hydrolyse a structurally similar naphthyl ester. In addition to heteroatom discrimination one of the antibodies examined in detail displayed an increase in catalytic efficiency presumably via weak apparent binding (Km) when phenylesters were employed as substrates. These findings suggest abzyme catalysis may be improved via substrate attenuation.

Electron spin resonance study of intermetallic molecules cum and aum (M = Mg, Zn, Cd and Hg)

A series of intermetallic diatomic molecules, CuM and AuM (M = Mg, Zn, Cd and Hg) generated in argon matrices was examined by e.s.r. spectroscopy. For all the CuM and AuM examined, the hyperfine coupling tensors to the Cu and Au nuclei were isotropic. The unpaired electron resides in an orbital given essentially by an antibonding combination of the valence s orbitals of Cu (or Au) and M atoms. Coupling interactions observed with magnetic Cd and Hg nuclei, and the analysis of the g tensor indicate a small admixture (≈ 10%) of the valence pz orbital of the atom M in each CuM and AuM examined.