Simon J. Teague

Synthesis and study of a non macrocyclic FK506 derivative

Abstract The affinity of a non macrocyclic analogue of FK506 for the immunophilin FKBP12 was determined The affinity of this analogue/FKBP12 complex for calcineurin was studied.

Synthesis and evaluation of dual domain macrocyclic FKBP12 ligands.

Abstract A number of dual domain, macrocyclic FKBP12 ligands were synthesised in which the FK506 effector domain was fused to simplified FKBP12 bindings domains. The resulting macrocyclic compounds possessed moderate binding affinities for FKBP12 but showed no activity in an assay for FKBP12 dependent calcineurin inhibition.

The contribution to binding of the pyranoside substituents in the excised binding domain of FK-506

Abstract The contributions of the C-11 methyl and C-13 / C-15 methoxy substituents to the affinity of FK-506 for the immunophilin FKBP-12 were investigated. Substraction of the C-11 methyl group led to a 400-fold drop in affinity. Removal of the C-13 and C-15 methoxy substituents led to a much smaller drop in affinity.

Synthetic FKBP12 ligands. Design and synthesis of pyranose replacements.

Abstract A number of FKBP12 ligands were designed and synthesised and their affinity for FKBP12 assessed. In these ligands the pyranose ring of FK506 was replaced by other more synthetically accessible groups. The preparation of suitable intermediates for the synthesis of “dual domain” inhibitors (compounds 6a–c, 15 and 22) is also described.

Macrocyclic ring closures employing the Intramolecular Heck reaction

Abstract Intramolecular Heck reactions have been employed for the final ring closure step in the construction of a series of macrocyclic compounds.

Synthesis of FK506-Cyclosporin hybrid macrocycles

Abstract An attempt was made to synthesise calcineurin inhibitors using dual domain macrocyclic compounds that incorporated a FKBP12 binding domain together with a calcineurin recognition domain which had been designed by consideration of the relevant features of both FK506 and Cyclosporin A.

The affinity of the excised binding domain of FK-506 for the immunophilin FKBP12

Abstract The affinity of the binding domain of FK-506 was determined, in the absence of the constraints imposed upon it by the macrocyclic framework. Removal of those parts of FK-506 not involved in the binding of FK-506 to FKBP12 results in a 50-fold drop in affinity.

A new synthesis of FPL 64176 and analogues: The discovery of benzoylpyrrole calcium channel activators with low nanomolar potency

Abstract Heavy metal assisted halogen displacement on 2-halobenzoylpyrroles (2 and 3) leads to a simple synthesis of FPL 64176 (1) and a variety of analogues (4–10). The difluoro derivative (4). EC50 1nM, and the amino linked analogue (7), EC50 2.7nM, are presently the most potent calcium channel activators known.