Mark Peter Ridgill

2-Aryl indole NK1 receptor antagonists: optimisation of the 2-Aryl ring and the indole nitrogen substituent

Novel 2-aryl indole hNK1 receptor ligands were prepared utilising palladium cross-coupling chemistry of a late intermediate as a key step. Compounds with high hNK1 receptor binding affinity and good brain penetration (e.g., 9d) were synthesised.

Synthesis and sar of 2- and 3-substituted 7-azaindoles as potential dopamine D4 ligands.

7-azaindole compounds bearing a cyclic amine moiety linked by a one or two carbon chain attached at the 2- or 3-position were synthesised and evaluated as potential dopamine D4 ligands. Highest affinity and selectivity for the D4 receptor resided in the 3-aminomethyl-7-azaindole series.

Amino acid bioisosteres: design of 2-quinolone derivatives as glycine-site N-methyl-D-aspartate receptor antagonists

Abstract 3-Substituted-2-quinoloners ( 6–8 ) have been identified as glycine-site N-methyl-D-aspartate receptor antagonists. It is proposed that the α-phenyl lactam unit in the potent 4-hydroxy-3-phenyl derivatives ( 7d and 8b , L-701,315) may act as a glycine bioisostere in receptor recognition.

4,4-Disubstituted cyclohexylamine NK1 receptor antagonists II

Abstract A series of novel 4,4-disubstituted cyclohexylamine based NK 1 antagonists is described. The effect of changes to the C 1 –C 4 relative stereochemistry on the cyclohexane ring and replacements for the flexible linker are discussed, leading to the identification of compounds with high affinity and good in vivo duration of action.

Synthesis and SAR of diiodotyrosine-derived glycine-site N-methyl-D-aspartate receptor ligands

Abstract A series of analogues of the novel diiodotyrosine derived NMDA glycine-site ligand (R)-4 was prepared in which the aryl substitution, chain length and amino acid groups were varied. The key structural features for binding are the α-amino acid function, having the (R) absolute stereochemistry, the 3,5-diiodo substituted aromatic ring and a lipophilic group attached at the phenolic oxygen of the tyrosine moiety.

4-Heterocyclyl tetrahydropyridines as selective ligands for the human dopamine D4 receptor

Abstract A series of 1,2,3,6-tetrahydropyridines 3 were synthesised, which resulted in selective high affinity dopamine D4 ligands. The SAR of heterocyclic replacements and aromatic substitution was investigated, leading to compounds of nanomolar binding affinity with excellent selectivity over both D2 and D3 receptors.

2-Aryl indole NK1 antagonists: optimisation of the amide substituent

The in vivo properties of a series of 2-arylindole NK(1) antagonists have been improved, by modification of the amide substituent. The 1-(2-methoxyphenyl)piperazine amide was identified as a major area of metabolism in the lead compound 1. Replacement of this amine moiety by a 4-benzyl-4-hydroxypiperidine resulted in a compound 18 with reduced clearance and improved central duration of action.