Michael Richard Attwood

The design and synthesis of the Angiotensin Converting Enzyme inhibitor Cilazapril and related bicyclic compounds

The postulated binding functions for the active site of Angiotensin Converting Enzyme (A.C.E.), derived in an earlier study, have made possible the design of improved inhibitors. Consequently, (1S,9S)-9-[(1S)-(ethoxycarbonyl)-3-phenylpropylamino]octahydro-10-oxo-6H-pyridazo[1,2-a][1,2]diazepine-1-carboxylic acid (Cilazapril), and related compounds, have been synthesized. They are very active inhibitors of A.C.E. and are highly potent antihypertensives in vivo.

New potent inhibitors of angiotensin converting enzyme

Using an earlier model of the favoured orientation of binding functions of angiotensin converting enzyme (ACE) inhibitors, it has been possible to postulate a new, 7,6‐bicyclic system, based on hexahydropyridazine, which might be expected to have high potency. Some members of this system which have been synthesised have been shown to be very active ACE inhibitors, in vitro and in vivo.

A new synthetic equivalent of the glutamic acid γ-anion and its application to the synthesis of S-(+)-γ-carboxyglutamic acid

Abstract Protected S-pyroglutamic acid can be deprotonated specifically at the γ-position. The resulting enolate can be converted into γ-carboxyglutamic acid in optically pure form.

Peptide based inhibitors of interleukin-8: structural simplification and enhanced potency

Abstract Important areas of a lead peptide inhibitor of IL-8 had been previously identified. Chemical modification led to the identification of key amide bonds which allowed the replacement of the central section of the peptide with modified amino acids and spacers. This approach led to inhibitors of lower molecular weight and of increased potency.

A stereospecific synthesis of 2-oxabicyclo[3.1.0]hexanes

Abstract A stereospecific 1,3-elimination reaction of γ-hydroxy stannanes has been employed in the synthesis of 2-oxabicyclo[3.1.0]hexanes.

Synthesis of the potent potassium channel opener Ro 31-6930 via claisen rearrangement and tandem regiocontrolled cyclisation.

Abstract The synthesis of the potent potassium channel opener Ro 31-6930 is reported. Methods of controlling the regiochemistry of the crucial cyclisation are described.

Identification and characterisation of an inhibitor of interleukin-8: a receptor based approach

Abstract Identification of the extracellular domains of the interleukin-8 (IL-8) receptor led to the synthesis of several peptide sequences. A peptide derived from a single subdomain was shown to inhibit IL-8 binding and to act as a functional antagonist. Ala-scan and truncation strategies identified key areas of this peptide for further work.

On the aldol reactions of β - (tri - n -butylstannyl)propionates

Abstract Steric rather than electrostatic interactions have been shown to be the controlling factor in the stereochemistry of enolate generation of β-trialkylstannylpropionates.

Aldol reactions of methyl (2-tributylstannyl)tetrahydrofuran-3-ylcarboxylate lithium enolate

Abstract The aldol reactions and subsequent transmetallation of β-stannylpropionates is described.

Synthesis of homochiral potassium channel openers: role of the benzopyranyl 3-hydroxyl group in cromakalim and pyridine N-oxides in determining the biological activities of enantiomers

Abstract The preparation of several homochiral benzopyranyl potassium channel openers is described. A subtle stereochemical effect of the 3-hydroxyl group on the biological activities of the enantiomers was observed.