Synthesis and evaluation of cis-hexahydropyrrolo[3,2-b]pyrrol-3-one peptidomimetic inhibitors of CAC1 cysteinyl proteinases.
A stereoselective synthesis of functionalised cis-hexahydropyrrolo[3,2-b]pyrrol-3-ones has been developed through Fmoc and Cbz-protected intermediates 5 and 6. Building blocks 5 and 6 were prepared via the intramolecular cyclisation of anti-epoxide 17. The intramolecular reaction occurred exclusively through the anti-epoxide to provide the 5,5-cis-fused bicycle, whereas the syn-epoxide, which theoretically would provide the 5,5-trans-fused bicycle, remained unchanged. These experimental observations are consistent with a key design element that we have introduced within this novel bicyclic ketone scaffold. Our bicyclic design strategy provides chiral stability to the bridgehead stereocentre that is situated alpha to the ketone because the cis-fused geometry is both thermodynamically and kinetically stable. Building blocks 5 and 6 have been utilised in both solid phase and solution phase syntheses of peptidomimetics 22, 36-40, which exhibit potent in vitro inhibition against a range of CAC1 cysteinyl proteinases. Compound 22, a potent and selective inhibitor of human cathepsin K exhibited good primary DMPK properties along with promising activity in an in vitro cell-based human osteoclast assay of bone resorption.
Quibell
Martin
M
Amura Therapeutics Limited, Incenta House, Horizon Park, Barton Road, Comberton, Cambridge CB37AJ, UK. martin.quibell@incenta.co.uk
Benn
Alex
A
Flinn
Nick
N
Monk
Tracy
T
Ramjee
Manoj
M
Ray
Peter
P
Wang
Yikang
Y
Watts
John
J
D002851:Chromatography, High Pressure Liquid; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D018716:Molecular Mimicry; D010006:Osteoblasts / Q000187:drug effects / Q000201:enzymology; D011758:Pyrroles / Q000138:chemical synthesis* / Q000494:pharmacology; D013057:Spectrum Analysis
D015853:Cysteine Proteinase Inhibitors; D011758:Pyrroles