Kirsteen Buchanan

2-O-substituted cyclodextrins as reversal agents for the neuromuscular blocker rocuronium bromide.

A series of secondary face modified cyclodextrins (CDs) were synthesised with the aim of constructing host molecules capable of forming host-guest complexes with neuromuscular blockers, especially with rocuronium bromide. Perfacial 2-O-substitution of gamma-CD with 4-carboxybenzyl resulted in a CD host molecule 1 that forms a 1:1 binary complex with rocuronium bromide (K(a) 6.2 x 10(5) M(-1)). The biological activities of this compound and other derivatives as reversal agents of rocuronium bromide were examined in vitro (mouse hemi-diaphragm) and in vivo (anaesthetized guinea pigs). The host molecule 1 was found to exert potent reversal activity (ED(50) 0.21 micromol/kg, iv) against rocuronium-induced neuromuscular block, and thus proved the viability of using host molecules as antidotes of a biologically active compound.

Water-soluble propofol analogues with intravenous anaesthetic activity

Propofol (2,6-diisopropylphenol) is a widely used intravenous anaesthetic that is formulated as an emulsion since it lacks water solubility. We report a range of water-soluble analogues of propofol, containing a para-alkylamino substituent, which retain good intravenous anaesthetic activity in rodents.

Novel water soluble 2,6-dimethoxyphenyl ester derivatives with intravenous anaesthetic activity.

A number of water soluble bis-amino-2,6-dimethoxyphenyl ester derivatives were found to exhibit improved anaesthetic activity in mice relative to propofol 1. Of the analogues disclosed, 44 was further profiled in rodents and found to be a superior agent to propofol for the induction and maintenance of anaesthesia.

The discovery of novel indole-2-carboxamides as cannabinoid CB1 receptor antagonists

The discovery and structure-activity relationship of a novel series of indole-2-carboxamide antagonists of the cannabinoid CB(1) receptor is disclosed. Compound 26i was found to be a high potency, selective cannabinoid CB(1) antagonist.

Pharmacokinetic optimisation of novel indole-2-carboxamide cannabinoid CB1 antagonists

The pharmacokinetic based optimisation of a novel series of indole-2-carboxamide antagonists of the cannabinoid CB(1) receptor is disclosed. Compound 24 was found to be a highly potent and selective cannabinoid CB(1) antagonist with high predicted human oral bioavailability.

Optimisation of pharmacokinetic properties to afford an orally bioavailable and selective V1A receptor antagonist

The previously described lead compound 5 is a potent and selective V(1A) antagonist with affinity at both the rat and human receptor, but displays poor oral bioavailability and moderate clearance. We report herein the successful optimisation of the pharmacokinetic (PK) properties to afford the potent, selective, orally bioavailable and CNS penetrant compound 15f. A custom optimisation approach was required which demonstrated the value of using early, rapid in vivo PK studies to show improvements in oral exposure. Such assays may be of particular value where low oral bioavailability is anticipated to be multifactorial (e.g., permeability, gut wall metabolism and/or transport) where satisfactory modelling of in vitro data is likely to be difficult within a drug discovery context.

The discovery of novel 8-azabicyclo[3.2.1]octan-3-yl)-3-(4-chlorophenyl) propanamides as vasopressin V1A receptor antagonists

The discovery of a novel series of 8-azabicyclo[3.2.1]octan-3-yl)-3-(4-chlorophenyl) propanamide antagonists of the vasopressin V(1A) receptor is disclosed. Compounds 47 and 48 were found to be high affinity, selective vasopressin V(1A) antagonists.

Enantiospecific enzyme-catalysed resolution of novel N,N-disubstituted α-amino acid phenolic ester derivatives using pig liver esterase

R-Amino acid esters 1, 2 and 3 are novel compounds possessing hypnotic activity. On attempting an asymmetric synthesis of these molecules, racemisation was observed when reacting bis(2-methoxyethyl)amine with α-bromo intermediate 4. In vitro plasma stability studies showed that the R enantiomers had much greater resistance to esterase-mediated degradation than the corresponding S enantiomers. This observation led to the use of commercially available pig liver esterase to prepare 1, 2 and 3 on a multigram scale. The crystal structures of 1 and 2 are reported and confirm R configuration.

Novel α-amino-acid phenolic ester derivatives with intravenous anaesthetic activity

A novel series of α-amino-acid phenolic ester derivatives containing sulphide, sulphoxide, sulphone, ester and amide side chains were prepared and shown to display potent intravenous anaesthetic activity.