Phenoxyphenyl sulfone N-formylhydroxylamines (retrohydroxamates) as potent, selective, orally bioavailable matrix metalloproteinase inhibitors.
A novel series of sulfone N-formylhydroxylamines (retrohydroxamates) have been investigated as matrix metalloproteinases (MMP) inhibitors. The substitution of the ether linkage of ABT-770 (5) with a sulfone group 13a led to a substantial increase in activity against MMP-9 but was accompanied by a loss of selectivity for inhibition of MMP-2 and -9 over MMP-1 and diminished oral exposure. Replacement of the biphenyl P1' substituent with a phenoxyphenyl group provided compounds that are highly selective for inhibition of MMP-2 and -9 over MMP-1. Optimization of the substituent adjacent to the retrohydroxamate center in this series led to the clinical candidate ABT-518 (6), a highly potent, selective, orally bioavailable MMP inhibitor that has been shown to significantly inhibit tumor growth in animal cancer models.
Wada
Carol K
CK
Cancer Research Area, Abbott Laboratories, Department 47J, Building AP10, 100 Abbott Park Road, Abbott Park, Illinois 60064-6100, USA. carol.wada@abbott.com
Holms
James H
JH
Curtin
Michael L
ML
Dai
Yujia
Y
Florjancic
Alan S
AS
Garland
Robert B
RB
Guo
Yan
Y
Heyman
H Robin
HR
Stacey
Jamie R
JR
Steinman
Douglas H
DH
Albert
Daniel H
DH
Bouska
Jennifer J
JJ
Elmore
Ildiko N
IN
Goodfellow
Carole L
CL
Marcotte
Patrick A
PA
Tapang
Paul
P
Morgan
Douglas W
DW
Michaelides
Michael R
MR
Davidsen
Steven K
SK
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D002460:Cell Line; D005559:Formamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D006898:Hydroxylamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D008252:Macaca fascicularis; D061965:Matrix Metalloproteinase Inhibitors; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D051379:Mice; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D005559:Formamides; D006898:Hydroxylamines; D061965:Matrix Metalloproteinase Inhibitors; C443806:N-(1-(2,2-dimethyl-1,3-dioxol-4-yl)-2-((4,4-(trifluoromethoxyphenoxy)phenyl)sulfonyl)ethyl)-N-hydroxyformamide; D011480:Protease Inhibitors; D014409:Tumor Necrosis Factor-alpha; D008666:Metalloendopeptidases