title: 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.
abstract: 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.
authors.affiliation: Amura Therapeutics Limited, Incenta House, Horizon Park, Barton Road, Comberton, Cambridge CB3 7AJ, UK.
authors.forename: Yikang
authors.initials: Y
authors.lastname: Wang
authors.forename: Alex
authors.initials: A
authors.lastname: Benn
authors.forename: Nick
authors.initials: N
authors.lastname: Flinn
authors.forename: Tracy
authors.initials: T
authors.lastname: Monk
authors.forename: Manoj
authors.initials: M
authors.lastname: Ramjee
authors.forename: John
authors.initials: J
authors.lastname: Watts
authors.forename: Martin
authors.initials: M
authors.lastname: Quibell
mesh_terms: 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
chemical_list: 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