David C. Horwell

PD 176252: The first high affinity non-peptide gastrin-releasing peptide (BB2) receptor antagonist

In this paper we describe the development of a novel series of non-peptide, balanced neuromedin-B preferring (BB1)/gastrin-releasing peptide preferring (BB2) receptor ligands as exemplified by PD 176252. PD 176252, which exhibits nanomolar affinity for both the BB1 (Ki = 0.15 nM) and BB2 (Ki = 1.0 nM) receptors, has been demonstrated to be a competitive antagonist at these bombesin receptor subtypes.

PD 165929 — the first high affinity non-peptide neuromedin-B (NMB) receptor selective antagonist

Abstract In this paper we describe the development of a novel series of non-peptide neuromedin-B (NMB) receptor ligands as exemplified by PD 165929. PD 165929, which exhibits nanomolar affinity for the NMB receptor (Ki=6.3nM), has been demonstrated to be a competitive antagonist at this receptor (appK B =7.6nM) and is selective over the corresponding gastrin-releasing peptide (GRP) receptor type (Ki>10000nM).

Regioselective nucleophilic ring opening reactions of 2,2-disubstituted aziridines — the asymmetric synthesis of α,α-disubstituted amino acids

Abstract In this paper a broadly applicable synthesis of chiral α,α-disubstituted amino acids is outlined based upon regioselective ring opening of aziridine derivatives. Examples of nitrogen, sulphur and carbon nucleophiles were found to preferentially attack the C3 position of chiral 2-methyl-2-silyloxymethyl aziridines to provide a range of α,α-disubstituted amino acid derivatives in good yield.

Synthesis and biological evaluation of conformationally restricted Gabapentin analogues.

A series of conformationally restricted Gabapentin analogues has been synthesised. The pyrrolidine analogue (R)-2-Aza-spiro[4.5]decane-4-carboxylic acid hydrochloride (3a) had an IC50 of 120 nM, similar to that of Gabapentin (IC50 = 140 nM), at the Gabapentin binding site on the alpha2delta subunit of a calcium channel. Compound (3a) also reversed carrageenan induced hyperalgesia in rats.

A Convenient and Versatile Method for the Synthesis of Protected Guanidines

Abstract Aromatic, aliphatic and sterically hindered amines react smoothly with commercially available N, N-bis-BOC-S-methylisothiourea 2 in the presence of mercury chloride to give the protected guanidine in good yield. It is particularly noteworthy that 2 can also be employed in a straightforward, two-step synthesis of monoaryl internal guanidines.

The Use of Heterocycles for the Conformational Restriction of Biologically Active Peptoids

Abstract A series of piperazinone ring systems have been synthesised as a means of evaluating the effect of conformational restriction on high affinity non-peptide NK1, NK3 and CCK-B receptor ligands. The synthesis of the targeted heterocycles is described along with a discussion of their affinities for their respective receptor types.

Dendroid Peptide Structural Mimetics of ω-Conotoxin MVIIA based on a 2(1H)-Quinolinone Core

Abstract Three mimetics of the peptide ω-Conotoxin MVIIA have been synthesised following the dendroid approach. The three key central amino acids of the natural peptide are mimicked by phenylguanidine (arginine), isopentyl (leucine) and aryl alcohol (tyrosine) attached to a quinolinone core at the 1- and 8-positions. The derivatives are designed to position these key groups in similar spatial orientation to that of the natural peptide in a structure that will have limited conformational flexibility. Key steps of the syntheses involve selective N -alkylation of quinolinone derivatives and guanylation of aryl amines.

N- vs. O-Alkylation in 2(1H)-Quinolinone Derivatives.

Abstract N- vs O-alkylation reactions of 8-benzyloxy-2(1H)-quinolinone have been investigated using both classical and phase transfer conditions. The influence of reaction solvents/conditions was found to have a dramatic effect on selectivity, with opposite trends to that observed for 2-pyridone alkylation.

Investigation into the preferred conformation of gabapentin for interaction with its binding site on the α2δ subunit of a calcium channel

Abstract A series of conformationally restricted Gabapentin analogues has been synthesised and used to propose the preferred conformation of Gabapentin for it to bind to the α 2 δ subunit of a calcium channel.

2,3-Substituted 2-azanorbornanes as polar β-turn mimetics

The design and synthesis of N -(3-indolylmethyl)-3-benzyl-2-azabicyclo[2.2.1]heptane-2-carboxamide ( 3 ) as a conformationally constrained non-peptide β-turn mimetic is described. Compound 3 is shown to mimic the Trp and Phe side chain conformation and the overall dipole moment of MEN10627 ( 2 ), a cyclic hexapeptide with a high NK-2 affinity. The tachykinin receptor affinities of 3 are evaluated and compared to those of MEN10627 and previously reported Trp-Phe mimetic 1 .