Richard S. Todd

Antagonists of the human A(2A) adenosine receptor. 4. Design, synthesis, and preclinical evaluation of 7-aryltriazolo[4,5-d]pyrimidines.

Antagonism of the human A(2A) receptor has been implicated as a point of therapeutic intervention in the alleviation of the symptoms associated with Parkinsons disease. This is thought to occur, at least in part, by increasing the sensitivity of the dopaminergic neurons to the residual, depleted levels of striatal dopamine. We herein describe a novel series of functionalized triazolo[4,5-d]pyrimidine derivatives that display functional antagonism of the A(2A) receptor. Optimization of these compounds has resulted in improvements in potency, selectivity, and the pharmacokinetic properties of key derivatives. These efforts have led to the discovery of 60 (V2006/BIIB014), which demonstrates strong oral activity in commonly used models of Parkinsons disease. Furthermore, this derivative has shown excellent preclinical pharmacokinetics and has successfully completed phase I clinical studies. This compound is presently undergoing further clinical evaluation in collaboration with Biogen Idec.

Structure-activity relationships of the peptide deformylase inhibitor BB-3497: Modification of the metal binding group

A series of analogues of the potent peptide deformylase (PDF) inhibitor BB-3497 containing alternative metal binding groups was synthesised. Enzyme inhibition and antibacterial activity data for these compounds revealed that the bidentate hydroxamic acid and N-formyl hydroxylamine structural motifs represent the optimum chelating groups on the pseudopeptidic BB-3497 backbone.

The synthesis and biological evaluation of non-peptidic matrix metalloproteinase inhibitors

Novel sulfonamide matrix metalloproteinase inhibitors of general formula (9) were synthesised by a route involving a stereoselective conjugate addition reaction. Enzyme selectivity was found to be dependant on the nature of the sulfonamide substituents. Compounds (9f, 9q) are potent selective collagenase inhibitors with good oral bioavailability.

The synthesis of novel matrix metalloproteinase inhibitors employing the Ireland-Claisen rearrangement

Matrix metalloproteinase inhibitors of general formula (1) were synthesised by a route involving an Ireland-Claisen rearrangement which enables systematic modification of the substituent alpha to the hydroxamic acid. An analogue (12c) possessing an alpha-cyclopentyl group is a potent broad spectrum inhibitor that displays high and sustained blood levels following oral dosing in both the rat and marmoset ex-vivo bioassays. This compound and analogues are also potent inhibitors of TNF alpha release.

Asymmetric synthesis of bb-3497—A potent peptide deformylase inhibitor

By screening a library of metalloenzyme inhibitors, the N-formyl-hydroxylamine derivative BB-3497 was identified as a potent inhibitor of Escherichia coli peptide deformylase with antibacterial activity both in vitro and in vivo. The homochiral synthesis of BB-3497, involving a novel asymmetric Michael addition reaction is described.

Triazinylaniline derivatives as fluorescence probes. Part 1. Absorption and fluorescence in organic solvents and in aqueous media in relation to twisted intramolecular charge-transfer state formation, hydrogen bonding, and protic equilibria

The UV absorption and fluorescence characteristics of new optical probes based on a 1,3,5-triazinylaniline chromophore and of general structure p-Et2NC6H4C3N3(Cl)NR1R2 are reported. Increase in alkanol solvent polarity strongly quenches the fluorescence by a process attributed to TlCT (twisted intramolecular charge-transfer) state formation with co-operative solvent relaxation (log kNR/s–1 8.5–10.5). In aqueous media no changes in fluorescence band position or intensity are observed in the pH range 3.5 to 11 but below pH 3.5 protonation of the anilino nitrogen (pKaca. 2.4) eliminates both the λ= 360 nm absorption band and the weak λ= 460 nm fluorescence band. Free and hydrogen-bonded species, with respect to the anilino nitrogen centre, are present in aqueous dioxane solutions.The triazinylaniline derivatives are prototypes of promising sensitive probes for organized media and as models of proteins labelled with the triazinylaniline fluorophore.

The design and biological evaluation of a series of 3-hydroxy-3-methylglutaryl coenzyme a (HMG-CoA) reductase inhibitors related to dihydromevinolin.

Abstract HMG-CoA reductase inhibitors structurally related to dihydromevinolin have been designed and tested. It has been shown that for high inhibitory potency these compounds must possess a methyl group at the C-7 position, but several different alkenes can be tolerated at the C-3 position. These compounds show good activity both in vitro and in vivo .

Stereoselective Michael addition of benzylamines to homochiral methylenebutanedioates

The Michael addition of benzylamine to the homochiral methylenebutanedioate 10 gave an adduct 11 in good yield with high stereoselectivity. By performing the reaction in methanol the (2R,3R) diastereoisomer 11 was obtained in 88% de, which was increased to 98% de after recrystallisation of the primary amine derivative 13. The ratio of diastereoisomers was reversed by performing the reaction in aprotic solvents, with the (2R,3S) diastereoisomer 12 being obtained in 40% de in tetrahydrofuran. The Michael adduct 11 is formed under kinetic control. The primary amine 15 is a key intermediate in the synthesis of novel matrix metalloproteinase inhibitors.

Triazinylaniline (TA) derivatives as fluorescence probes. Part 2. Steady-state and time-resolved fluorescence anisotropy studies of TA probes in alkanols and in small unilamellar vesicles of phospholipids

The fluorescence behaviour is reported of three functionalized triazinylaniline, TA, dye probes p-Et2C6H4C3N3(Cl)N(Me)X, where X = C4H7, C18H37 and CH2[CHOH]4CH2OH, solubilized in small unilamellar vesicles of dimyristoyl- and dipalmitoyl-L-α-phosphatidylcholines, DMPC and DPPC respectively, and of DMPC–DPPC binary mixtures.Steady-state fluorescence yields (ca. 0.15) and anisotropies monitor the phospholipid phase transitions; the glucamine dye probe sensitively reflects the rearrangement of phospholipid head groups in the pre-transition region and probably resides in the vicinity of the glycerol backbone. Fluorescence decays of the probes are complex (mean lifetimes ca. 1.2 ns), but are not influenced strongly by the nature of the lipid phase.For the vesicle-bound probes the fluorescence anisotropy decays rapidly (lifetime ca. 1 ns) from an initial high value (r= 0.30–0.32) to reach a plateau value (range 0.0–0.24) indicative of a restricted angular rotation of the probes which has been related to the nature of the probe tail; in alkanols the anistropic decay is monoexponential and the pseudo-isotropic rotation rate varies linearly with solvent viscosity.