David W. Gordon

Reductive alkylation on a solid phase: Synthesis of a piperazinedione combinatorial library

Abstract The synthesis of a prototype trisubstituted piperazinedione combinatorial library of 1,000 compounds has been achieved from three precursor sets — two sets of ten α-amino acids and one set of ten aldehydes. A sodium triacetoxyborohydride-mediated reductive alkylation was crucial to the success of the multi-step synthesis on resin. This protocol represents a new method to augment compound files rapidly with novel heterocyclic entities for high-speed screening.

The combinatorial synthesis of a 30,752-compound library: discovery of SAR around the endothelin antagonist, FR-139,317

Abstract A combinatorial library of 30,752 compounds has been synthesised from a set of 32 natural and unnatural amino acids. The library was designed to include the known endothelin antagonist, FR-139,317, as a positive control, and this and a number of close analogues were shown to be the most potent compounds. Thus, combinatorial libraries may be used both to discover leads and rapidly explore SAR. A combinatorial library of 30,752 compounds has been synthesised from a set of 32 natural and unnatural amino acids. The library was designed to include the known endothelin antagonist, FR-139,317, as a positive control, and this and a number of close analogues were shown to be the most potent compounds. Thus, combinatorial libraries may be used both to discover leads and rapidly explore SAR.

Design and synthesis of piperazinylpyrimidinones as novel selective 5-HT2c agonists

This Letter reports the design and synthesis of several novel series of piperazinyl pyrimidinones as 5-HT(2C) agonists. Several of the compounds presented exhibit good in vitro potency and selectivity over the closely related 5-HT(2A) and 5-HT(2B) receptors. Compound 11 was active in in vivo models of stress urinary incontinence.

The design and discovery of novel amide CCR5 antagonists.

The synthesis of a range of novel amine-containing structures and their primary potency as inhibitors of HIV-1 fusion via blocking of the CCR5 receptor is described. The development of the medicinal chemistry strategy and SARs which led to the identification of the piperidine amide compounds 33 and 36 as excellent leads for further evaluation is described, along with key physicochemical data which highlighted their lead potential.

A Convenient Route to Tropolone Ethers

Abstract A general synthesis of tropolone ethers employing the reaction of tropolone with potassium carbonate, an alkyl halide and dicyclohexyl-18-crown-6 in acetonitrile solvent is described.

Design and optimisation of selective serotonin re-uptake inhibitors with high synthetic accessibility: part 2.

A second wave of potential SSRIs with high ease of synthetic accessibility were designed based on the reported selective serotonin re-uptake inhibitor litoxetine and our own previous work in this area. Preparation and subsequent optimisation yielded a range of potent and highly selective SSRIs.

Expeditious One-Pot, Four-Step Preparation of 2-t-Butoxycarbonyl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline and an Improved Conversion to Its 6-Cyano Derivative

3-Methoxy-phenethylamine was subjected to a sequential imination/Pictet–Spengler/demethylation/Boc protection sequence that allowed a one-pot preparation of N-Boc-6-hydroxy-1,2,3,4-tetrahydroisoquinoline 1. This intermediate was elaborated almost quantitatively via an improved triflation/cyanation procedure to its 6-cyano analog 2.