David Alexander Learmonth

Discovery of a Long-Acting, Peripherally Selective Inhibitor of Catechol-O-methyltransferase

Novel nitrocatechol-substituted heterocycles were designed and evaluated for their ability to inhibit catechol-O-methyltransferase (COMT). Replacement of the pyrazole core of the initial hit 4 with a 1,2,4-oxadiazole ring resulted in a series of compounds endowed with longer duration of COMT inhibition. Incorporation of a pyridine N-oxide residue at position 3 of the 1,2,4-oxadiazole ring led to analogue 37f, which was found to possess activity comparable to entacapone and lower toxicity in comparison to tolcapone. Lead structure 37f was systematically modified in order to improve selectivity and duration of COMT inhibition as well as to minimize toxicity. Oxadiazole 37d (2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-3-yl)-4,6-dimethylpyridine 1-oxide (BIA 9-1067)) was identified as a long-acting, purely peripheral inhibitor, which is currently under clinical evaluation as an adjunct to L-Dopa therapy of Parkinsons disease.

Efficient Synthesis of 2-(Trifluoromethyl)nicotinic Acid Derivatives from Simple Fluorinated Precursors

Novel routes to 2-trifluoromethyl-nicotinic acid derivatives have been developed involving synthesis of the pyridine ring. These pyridyl compounds serve as key intermediates in the manufacture of the recently discovered COMT inhibitor, 3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-3-yl)-2-(trifluoromethyl)pyridine 1-oxide.

Synthesis, anticonvulsant properties and pharmacokinetic profile of novel 10,11-dihydro-10-oxo-5H-dibenz/b,f/azepine-5-carboxamide derivatives.

A series of novel derivatives of oxcarbazepine (5), 10,11-dihydro-10-oxo-5H-dibenz/b,f/azepine-5-carboxamide was synthesised and evaluated for their anticonvulsant activity and sodium channel blocking properties. The oxime 8 was found to be the most active compound from this series, displaying greater potency than its geometric isomer 9 and exhibiting also the highest protective index value. Importantly, the metabolic profile of 8 differs from the already established dibenz/b,f/azepine-5-carboxamide drugs such as 1 and 5 which undergo rapid and complete conversion in vivo to several biologically active metabolites. In contrast 8 is metabolised to only a very minor extent leading to the conclusion that the observed anti-convulsant effect is solely attributable to 8. It is concluded that 8 may be as effective as 1 and 5 at controlling seizures and that the low toxicity and consequently high protective index should provide the compound with an improved side-effect profile.

Design, synthesis, and structure–activity relationships of 1,3,4-oxadiazol-2(3H)-ones as novel FAAH inhibitors

Novel 5-aryloxy substituted 3-phenyl-1,3,4-oxadiazol-2(3H)-ones were prepared and identified as potent inhibitors of FAAH. In vitro SAR are discussed. Structural variations of the selected lead compound were explored in order to optimise in vivo efficacy and selectivity.

IMPROVED METHOD FOR DEMETHYLATION OF NITRO- CATECHOL METHYL ETHERS

ABSTRACT Several nitro-catechol compounds, useful as inhibitors of COMT were obtained in excellent yield and purity via an improved procedure for demethylation of the corresponding methyl ethers using aluminium chloride and pyridine in ethyl acetate.

The chemistry of catechol-O-methyltransferase inhibitors.

Despite several drawbacks, levodopa (L-dopa) remains the gold standard drug for treatment of the symptoms of Parkinsons disease (PD). L-dopa is a pro-drug of dopamine and is used to elevate striatal levels of the neurotransmitter. One approach to provide a more continuous and sustained delivery of dopamine has targeted one of the principal enzymes responsible for metabolic deactivation of L-dopa, namely catechol-O-methyltransferase (COMT). The chapter will provide a perspective of the medicinal chemistry behind the discovery of several COMT inhibitors and discuss how certain physicochemical parameters, including aqueous solubility and lipophilicity, are thought to influence pharmacokinetic properties such as absorption, distribution, and bioavailability.

A Novel, Convenient Synthesis of the 3‐O‐β‐D‐ and 4′‐O‐β‐D‐Glucopyranosides of trans‐Resveratrol

Abstract trans‐Resveratrol‐3‐O‐β‐D‐glucupyranoside (trans‐piceid, 2) and trans‐resveratrol‐4′‐O‐β‐D‐glucupyranoside (trans‐resveratroloside 3) are the naturally occurring O‐glucoside conjugates of the polyphenolic stilbenoid trans‐resveratrol 1. Recently, attention has been drawn towards the interesting biological properties of the glucoside conjugates 2 and 3 as well as those of the aglycone 1. The fact that only limited quantities can be obtained by extraction from natural sources has prompted the development of novel syntheses of 2 and 3, based on a convergent Heck‐coupling strategy, which now conveniently allows for the preparation of multi‐milligram to gram quantities of each.

RAPID MICROWAVE-PROMOTED SYNTHESIS OF FUNCTIONALISED BENZOPHENONES

ABSTRACT Several functionalised benzophenone derivatives have been conveniently obtained in moderate to good yield via the rapid, microwave-promoted Friedel–Crafts acylation of activated arenes with benzoic acids in polyphosphoric acid medium.

Synthesis and structure–activity relationships of ionizable 1,3,4-oxadiazol-2(3H)-ones as peripherally selective FAAH inhibitors with improved aqueous solubility

Abstract Novel 5-(2,4-difluorophenoxy)-3-aryl-1,3,4-oxadiazol-2(3H)-ones were prepared and in vivo SAR are discussed. Ionisable substituents on the N-phenyl ring provided compounds with significantly improved aqueous solubility. In addition, these analogues retained equivalent or improved potency against FAAH enzyme compared to the parent phenols 2–3. FAAH inhibition by the 2-(piperazin-1-yl)ethyl and 3-(piperazin-1-yl)propyl derivatives 24 and 30 was confined to the periphery in mice (30 mg/kg), whereas hepatic FAAH activity was inhibited by over 90%.