cis-6-oxo-hexahydro-2-oxa-1,4-diazapentalene and cis-6-oxo-hexahydropyrrolo[3,2-c]pyrazole based scaffolds: design rationale, synthesis and cysteinyl proteinase inhibition.
The 5,5-bicycles cis-6-oxo-hexahydro-2-oxa-1,4-diazapentalene 3 and cis-6-oxo-hexahydropyrrolo[3,2-c]pyrazole 4 were designed as rotationally restricted templates towards the preparation of inhibitors of CAC1 cysteinyl proteinases. The design strategy was exemplified through the solution and solid phase preparation of potent inhibitors of human cathepsin K and may potentially be applied to inhibitors of other CAC1 proteinases.
Wang
Yikang
Y
Amura Therapeutics Limited, Incenta House, Horizon Park, Barton Road, Comberton, Cambridge CB3 7AJ, UK.
Benn
Alex
A
Flinn
Nick
N
Monk
Tracy
T
Ramjee
Manoj
M
Watts
John
J
Quibell
Martin
M
D056657:Cathepsin K; D002403:Cathepsins / Q000037:antagonists & inhibitors; D003546:Cysteine Endopeptidases / Q000187:drug effects* / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D006574:Heterocyclic Compounds, 2-Ring / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008968:Molecular Conformation; D011485:Protein Binding / Q000187:drug effects; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D015853:Cysteine Proteinase Inhibitors; D006574:Heterocyclic Compounds, 2-Ring; D011720:Pyrazoles; D011758:Pyrroles; C501620:cis-6-oxo-hexahydro-2-oxa-1,4-diazapentalene; C501619:cis-6-oxo-hexahydropyrrolo(3,2-c)pyrazole; D002403:Cathepsins; D003546:Cysteine Endopeptidases; C534130:CTSK protein, human; D056657:Cathepsin K