Nicholas K. Terrett

Sildenafil (VIAGRATM), a potent and selective inhibitor of type 5 cGMP phosphodiesterase with utility for the treatment of male erectile dysfunction

Abstract 5-(2′-Alkoxyphenyl)pyrazolo[4,3-d]pyrimidin-7-ones, and in particular our preferred compound, sildenafil (VIAGRATM), discovered through a rational drug design programme, are potent and selective inhibitors of the type 5 cGMP phosphodiesterase from both rabbit platelets and human corpus cavernosum. Sildenafil is currently in the clinic for the oral treatment of male erectile dysfunction.

Comparison of algorithms for dissimilarity-based compound selection

Dissimilarity-based compound selection has been suggested as an effective method for selecting structurally diverse subsets of chemical databases. This article reports a comparison of several maximum-dissimilarity and sphere-exclusion algorithms for dissimilarity-based selection. The effectiveness of the algorithms is quantified by the numbers of biological activity classes identified in subsets selected from the World Drugs Index database, and by the numbers of active compounds identified in feedback searches of this database. The experiments demonstrate the general effectiveness and efficiency of the MaxMin algorithm.

Stereospecific syntheses and reactions of allyl- and allenyl-silanes

Abstract The stereospecifically anti synthesis of allyl- and allenyl-silanes by the reaction of a silylcuprate reagent with allyl and propargyl acetates is described. The S E 2′ reactions of these silanes with various electrophiles are shown to proceed with predominantly anti stereoselectivity, offset to a greater or lesser extent by other steric factors.

UK-69,578, a novel inhibitor of EC 3.4.24.11 which increases endogenous ANF levels and is natriuretic and diuretic

A search for potent inhibitors of EC 3.4.24.11, an enzyme which is found most abundantly in the kidney and which degrades atrial natriuretic factor, has led to the identification of UK-69,578. Structure-activity studies starting from substituted N-carboxymethyl dipeptide inhibitors resulted in the introduction of a cyclo-alkane P1 residue and in the replacement of the aza-link between P1 and P1 residues by a methylene group, with a net ten-fold potency gain. UK-69,578 increases endogenous ANF levels and produces natriuretic and diuretic responses intravenously in mice.

Parallel-compound synthesis: Methodology for accelerating drug discovery

Parallel compound synthesis enables large numbers of individual compounds to be prepared simultaneously using semiautomated techniques. This fast and efficient methodology has an important role to play in accelerating lead optimisation and hence the whole drug discovery process. The potential of this strategy to rapidly optimise chemical leads and provide structure-activity relationship (SAR) information was demonstrated in two therapeutic areas, antiviral agents (herpes simplex virus), and neurokinin-2 receptor antagonists.

The Discovery of Macrocyclic XIAP Antagonists from a DNA-Programmed Chemistry Library, and Their Optimization To Give Lead Compounds with in Vivo Antitumor Activity.

Affinity selection screening of macrocycle libraries derived from DNA-programmed chemistry identified XIAP BIR2 and BIR3 domain inhibitors that displace bound pro-apoptotic caspases. X-ray cocrystal structures of key compounds with XIAP BIR2 suggested potency-enhancing structural modifications. Optimization of dimeric macrocycles with similar affinity for both domains were potent pro-apoptotic agents in cancer cell lines and efficacious in shrinking tumors in a mouse xenograft model.

Radical cyclisations of imines and hydrazones

Abstract Radical cyclisation of sp 3 carbon-centred radicals onto imines and hydrazones provides a new method for the synthesis of 5- and 6-membered ring nitrogen heterocycles. Cyclisation onto the electrophilic carbon of the C=N group and 5- exo stereoelectronic selectivity are the dominating mechanistic parameters. The C-centred radical intermediates were generated from benzeneselenyl precursors using Bu 3 SnH.

Synthesis of spiroethers using radical cyclisations

Abstract A variety of spiroether products, including one bis-spiro compound, are available via a simple radical cyclisation route.

The stereochemistry of some SE2′ reactions of allyl- and allenylsilanes☆

Abstract The SE2′ reactions of 1 and 2 with a range of electrophiles are predominantly anti in the allylsilane portion of the molecule, but this is offset, to a greater or lesser extent, by axial or equatorial preferences in the ring system.

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.