Keith Adrian Murray Walker

Synthesis of 4'-cyanothymidine and analogs as potent inhibitors of HIV

Abstract 4′-Cyanothymidine inhibits HIV in A301 (Alex) cells with an IC 50 of 0.002 μM. The uridine and cytidine analogs show similiar potencies.

4′-Substituted nucleosides as inhibitors of HIV: an unusual oxetane derivative.☆

The fused oxetane derivative of thymidine 3a inhibits HIV replication in A301 (Alex) cells with remarkably low bone marrow toxicity.

Catecholamine modulatory effects of nepicastat (RS‐25560‐197), a novel, potent and selective inhibitor of dopamine‐β‐hydroxylase

1 Inhibitory modulation of sympathetic nerve function may have a favourable impact on the progression of congestive heart failure. Nepicastat is a novel inhibitor of dopamine‐β‐hydroxylase, the enzyme which catalyses the conversion of dopamine to noradrenaline in sympathetic nerves. The in vitro pharmacology and in vivo catecholamine modulatory effects of nepicastat were investigated in the present study. 2 Nepicastat produced concentration‐dependent inhibition of bovine (IC50=8.5±0.8 nM) and human (IC50=9.0±0.8  nM)dopamine‐β‐hydroxylase. The corresponding R‐enantiomer (RS‐25560‐198) was approximately 2–3 fold less potent than nepicastat. Nepicastat had negligible affinity (>10 μM) for twelve other enzymes and thirteen neurotransmitter receptors. 3 Administration of nepicastat to spontaneously hypertensive rats (SHRs) (three consecutive doses of either 3, 10, 30 or 100 mg kg−1, p.o.; 12 h apart) or beagle dogs (0.05, 0.5, 1.5 or 5 mg kg−1, p.o.; b.i.d., for 5 days) produced dose‐dependent decreases in noradrenaline content, increases in dopamine content and increases in dopamine/noradrenaline ratio in the artery (mesenteric or renal), left ventricle and cerebral cortex. At the highest dose studied, the decreases in tissue noradrenaline were 47%, 35% and 42% (in SHRs) and 88%, 91% and 96% (in dogs) in the artery, left ventricle and cerebral cortex, respectively. When tested at 30 mg kg−1, p.o., in SHRs, nepicastat produced significantly greater changes in noradrenaline and dopamine content, as compared to the R‐enantiomer (RS‐25560‐198), in the mesenteric artery and left ventricle. 4 Administration of nepicastat (2 mg kg−1, b.i.d, p.o.) to beagle dogs for 15 days produced significant decreases in plasma concentrations of noradrenaline and increases in plasma concentrations of dopamine and dopamine/noradrenaline ratio. The peak reduction (52%) in plasma concentration of noradrenaline and the peak increase (646%) in plasma concentration of dopamine were observed on day‐6 and day‐7 of dosing, respectively. 5 The findings of this study suggest that nepicastat is a potent, selective and orally active inhibitor of dopamine‐β‐hydroxylase which produces gradual modulation of the sympathetic nervous system by inhibiting the biosynthesis of noradrenaline. This drug may, therefore, be of value in the treatment of cardiovascular disorders associated with over‐activation of the sympathetic nervous system, such as congestive heart failure.

Solid-phase synthesis of Di- and tripeptidic hydroxamic acids as inhibitors of procollagen C-proteinase

A solid-phase approach to the rapid synthesis of di- and tripeptide-like hydroxamic acids is presented. These compounds are shown to be potent inhibitors of procollagen C-proteinase (PCP).

Amino acid derived sulfonamide hydroxamates as inhibitors of procollagen C-proteinase: solid-phase synthesis of ornithine analogues.

A discussion of the solid-phase synthesis of ornithine derived sulfonamide hydroxamic acids is illustrated. These analogues are shown to be potent, non-peptide inhibitors of procollagen C-proteinase (PCP).

Highly potent, non-basic 5-HT6 ligands. Site mutagenesis evidence for a second binding mode at 5-HT6 for antagonism.

A series of 5-HT(6) ligands derived from (R)-1-(amino)methyl-6-(phenyl)sulfonyltetralin was prepared that yielded several non-basic analogs having sub-nanomolar affinity. Ligand structure-activity relationships, receptor point mutation studies, and molecular modeling of these novel ligands all combined to reveal a new alternative binding mode to 5-HT(6) for antagonism.

Novel inhibitors of procollagen C-Proteinase. Part 2: glutamic acid hydroxamates☆

Glutamic acid derived hydroxamates were identified as potent and selective inhibitors of procollagen C-proteinase, an essential enzyme for the processing of procollagens to fibrillar collagens. Such compounds have potential therapeutic application in the treatment of fibrosis.

Amino acid derived sulfonamide hydroxamates as inhibitors of procollagen C-proteinase. Part 2: Solid-phase optimization of side chains

Optimization of the amino acid side chain and the N-alkyl group of the sulfonamide of amino acid derived sulfonamide hydroxamates is discussed. The solid-phase synthesis of these potent inhibitors of procollagen C-proteinase (PCP) is presented. In addition, novel carboxylic acid sulfonamides were discovered to be PCP inhibitors.

Novel inhibitors of procollagen C-terminal proteinase. Part 1: diamino Acid hydroxamates.

The parallel synthesis of novel inhibitors of procollagen C-terminal proteinase is described. The synthetic strategy allowed for the facile synthesis of a large number of side-chain diversified diamino acid hydroxamates, of which the D-diaminopropionic acid derivatives were shown to be single digit nanomolar PCP inhibitors.

Novel Series of Dihydropyridinone P2X7 Receptor Antagonists

Identification of singleton P2X7 inhibitor 1 from HTS gave a pharmacophore that eventually turned into potential clinical candidates 17 and 19. During development, a number of issues were successfully addressed, such as metabolic stability, plasma stability, GSH adduct formation, and aniline mutagenicity. Thus, careful modification of the molecule, such as conversion of the 1,4-dihydropyridinone to the 1,2-dihydropyridinone system, proper substitution at C-5″, and in some cases addition of fluorine atoms to the aniline ring allowed for the identification of a novel class of potent P2X7 inhibitors suitable for evaluating the role of P2X7 in inflammatory, immune, neurologic, or musculoskeletal disorders.