Barry Sidney Orlek

Stereoselective synthesis of protected amines and diamines from alkenes using N,N-Dichloro-t-butylcarbamate

N,N-Dichloro-t-butylcarbamate (1) reacts with alkenes (2) in a regio- and stereo-selective manner to give the trans-chlorocarbamate adducts (3). Treatment of (3) with base gives aziridines (5), and reaction of (3) and (5) with sodium azide leads selectively to the versatile diamine precursors (6) and (7).In situ reduction of (3) with Zn/NH4OAc leads directly to Boc-protected amines (10).

Characterisation of SB-221420-A — a neuronal Ca2+ and Na+ channel antagonist in experimental models of stroke

For progression to clinical trials in stroke, putative neuroprotective compounds should show robust efficacy post-ischaemia in several experimental models of stroke. This paper describes the characterisation of (+)(1S, 2R)-cis-1-[4-(1-methyl-1-phenylethyl)phenoxy]-2-methylamino indane hydrochloride (SB-221420-A), a Ca(2+) and Na(+) channel antagonist. SB-221420-A inhibited (IC(50)=2.2 microM) N-type voltage-operated Ca(2+) channel currents in cultured superior cervical ganglion neurons, which were pretreated with 10 microM nimodipine to block L-type voltage-operated Ca(2+) channel currents. In dorsal root ganglion neurons pretreated with 1 microM omega-conotoxin GVIA to block N-type voltage-operated Ca(2+) channel currents, SB-221420-A inhibited the residual Ca(2+) current with an IC(50) of 7 microM. SB-221420-A also inhibited Na(+) currents in dorsal root ganglion neurons with an IC(50) of 8 microM. In rats, the pharmacokinetic profile of SB-221420-A shows that it has a half-life of 6.4 h, a high volume of distribution, is highly brain penetrating, and has no persistent metabolites. Following bilateral carotid artery occlusion in gerbils, SB-221420-A significantly reduced the level of ischaemia-induced hyperlocomotor activity and the extent of hippocampal CA1 cell loss compared to the ischaemic vehicle-treated group. SB-221420-A was also effective in focal models of ischaemia. In the mouse permanent middle cerebral artery occlusion model, SB-221420-A (10 mg/kg) administered intravenously, post-ischaemia significantly (P<0.05) reduced lesion volume compared to the ischaemic vehicle-treated group. In the normotensive rat permanent middle cerebral artery occlusion model, SB-221420-A (10 mg/kg) administered intravenously over 1 h, beginning 30 min postmiddle cerebral artery occlusion, significantly (P<0.05) reduced lesion volume from 291+/-16 to 153+/-30 mm(3), compared to ischaemic vehicle-treated controls when measured 24 h postmiddle cerebral artery occlusion. Efficacy was maintained when the same total dose of SB-221420-A was infused over a 6-h period, beginning 30 min postmiddle cerebral artery occlusion. SB-221420-A also significantly (P<0.05) reduced lesion volume following transient middle cerebral artery occlusion in normotensive rats and permanent middle cerebral artery occlusion in spontaneously hypertensive rats (SHR). Investigation of the side effect profile using the Irwin screen in mice revealed that, at neuroprotective doses, there were no overt behavioural or cardiovascular changes. These data demonstrate that robust neuroprotection can be seen post-ischaemia with SB-221420-A in both global and focal ischaemia with no adverse effects at neuroprotective doses, and indicate the potential utility of a mixed cation blocker to improve outcome in cerebral ischaemia.

Steric acceleration of intramolecular cycloaddition reactions

Abstract Use of conformational constraints, induced by different ortho -substituents in 1-allyloxy-2-(substituted)methylbenzenes, where the substituent is a 1,3-dipole such as the azide or 3-oxidopyridinium group, can be employed to accelerate the 1,3-dipolar cycloaddition reaction. In this manner cycloadditions that otherwise do not proceed can be forced to react.

A stereoselective synthesis of 3-substituted hexahydroindeno[2,1-b]pyrroles via an intramolecular azomethine ylide cycloaddition

Abstract 3-Substituted hexahydroindeno[2,1-b]pyrroles were prepared in a stereoselective manner in high yield via an intramolecular azomethine ylide cycloaddition. Olefin geometry in the ylide precursor controlled the stereochemistry at the 3-position.

Design and synthesis of novel muscarinic agonists containing the 1,2,4-triazine ring as an ester bioisostere

Abstract Replacement of the ester group in methyl quinuclidine-3-car☐ylate1 with a 1,2,4-triazine ring afforded the high affinity muscarinic partial agonist6a. Analogues7a,7b and7d which incorporate the 1-azabicyclo[2.2.1]heptane ring also display high affinity for muscarinic receptors.

Identification of a series of 1,2,3,4-tetrahydroisoquinolinyl- benzamides with potential anticonvulsant activity

A series of N-(tetrahydroisoquinolinyl)-2-methoxybenzamides was identified by high-throughput screening at the novel SB-204269 binding site. SAR studies have provided compounds 4 and 14 with high affinity and good anticonvulsant activity in animal models.

Evaluation of a series of anticonvulsant 1,2,3,4-tetrahydroisoquinolinyl-benzamides.

SAR studies around a series of N-(tetrahydroisoquinolinyl)-2-methoxybenzamides, identified by high-throughput screening at the novel SB-204269 binding site, have provided compounds such as 13, 29-33 with high affinity and excellent anticonvulsant activity in animal models.

Design and synthesis of azabicyclic muscarinic agonists incorporating an oxime ether functionality

Abstract Replacement of the ester group of methyl quinuclidine-3-carboxylate 2 with an oxime ether afforded a series of potent muscarinic agonists with efficacies ranging from full to partial agonism. From an investigation of the relationship between central selectivity and efficacy, the propargyl ether 5g emerged as a high affinity partial agonist with a good separation between central and peripheral actions.

The discovery and optimisation of benzazepine sulfonamide and sulfones as potent agonists of the motilin receptor.

Optimisation of a series of benzazepine sulfonamide hit compounds identified from high throughput screening led to the discovery of a new series of tractable, potent motilin receptor agonists.

1,2,5,6-tetrahydropyridine oxime ethers incorporating electron withdrawing groups are potent and selective muscarinic agonists

Abstract The combination of N-methoxy imidoyl halide and nitrile moieties with the 1,2,5,6-tetrahydropyridine ring system afforded a novel series of potent muscarinic agonists. Members of this class, exemplified by the imidoyl nitriles 2c and 3c , show favourable central selectivity. The incorporation of fluoroacetyl oxime ethers gave compounds with weak affinity for muscarmic receptors.