4jpa
Mmp13 in complex with a piperazine hydantoin ligandMmp13 in complex with a piperazine hydantoin ligand
Structural highlights
Disease[MMP13_HUMAN] Defects in MMP13 are the cause of spondyloepimetaphyseal dysplasia Missouri type (SEMD-MO) [MIM:602111]. A bone disease characterized by moderate to severe metaphyseal changes, mild epiphyseal involvement, rhizomelic shortening of the lower limbs with bowing of the femora and/or tibiae, coxa vara, genu varum and pear-shaped vertebrae in childhood. Epimetaphyseal changes improve with age.[1] Defects in MMP13 are the cause of metaphyseal anadysplasia type 1 (MANDP1) [MIM:602111]. Metaphyseal anadysplasia consists of an abnormal bone development characterized by severe skeletal changes that, in contrast with the progressive course of most other skeletal dysplasias, resolve spontaneously with age. Clinical characteristics are evident from the first months of life and include slight shortness of stature and a mild varus deformity of the legs. Patients attain a normal stature in adolescence and show improvement or complete resolution of varus deformity of the legs and rhizomelic micromelia.[2] Function[MMP13_HUMAN] Degrades collagen type I. Does not act on gelatin or casein. Could have a role in tumoral process. Publication Abstract from PubMedPiperidine ether and aryl piperazine hydantoins are reported as potent inhibitors of MMP13. A medicinal chemistry campaign focused on replacing the reverse hydroxamate zinc binding group associated with historical inhibitors with a hydantoin zinc binding group then optimising MMP13 potency, solubility and DMPK properties whilst maintaining good selectivity over MMP14. A number of high quality candidates were progressed and following rat and dog safety evaluation, AZD6605 (3m) was identified as a candidate drug. Hydantoin based inhibitors of MMP13--discovery of AZD6605.,De Savi C, Waterson D, Pape A, Lamont S, Hadley E, Mills M, Page KM, Bowyer J, Maciewicz RA Bioorg Med Chem Lett. 2013 Aug 15;23(16):4705-12. doi:, 10.1016/j.bmcl.2013.05.089. Epub 2013 Jun 10. PMID:23810497[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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