NMR-based modification of matrix metalloproteinase inhibitors with improved bioavailability.
The NMR-based discovery of biaryl hydroxamate inhibitors of the matrix metalloproteinase stromelysin (MMP-3) has been previously described (Hajduk et al. J. Am. Chem. Soc. 1997, 119, 5818-5827). While potent in vitro, these inhibitors exhibited no in vivo activity due, at least in part, to the poor pharmacokinetic properties of the alkylhydroxamate moiety. To circumvent this liability, NMR-based screening was implemented to identify alternative zinc-chelating groups. Using this technique, 1-naphthyl hydroxamate was found to bind tightly to the protein (K(D) = 50 microM) and was identified as a candidate for incorporation into the lead series. On the basis of NMR-derived structural information, the naphthyl hydroxamate and biaryl fragments were linked together to yield inhibitors of this enzyme that exhibited improved bioavailability. These studies demonstrate that the NMR-based screening of fragments can be effectively applied to improve the physicochemical or pharmacokinetic profile of lead compounds.
Hajduk
Philip J
PJ
Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois 60064-3500, USA.
Shuker
Suzanne B
SB
Nettesheim
David G
DG
Craig
Richard
R
Augeri
David J
DJ
Betebenner
David
D
Albert
Daniel H
DH
Guo
Yan
Y
Meadows
Robert P
RP
Xu
Lianhong
L
Michaelides
Michael
M
Davidsen
Steven K
SK
Fesik
Stephen W
SW
D000818:Animals; D001682:Biological Availability; D020134:Catalytic Domain; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D019278:Matrix Metalloproteinase 3 / Q000737:chemistry; D061965:Matrix Metalloproteinase Inhibitors; D008958:Models, Molecular; D009281:Naphthalenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D011485:Protein Binding; D051381:Rats; D013329:Structure-Activity Relationship
D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; D009281:Naphthalenes; D011480:Protease Inhibitors; D019278:Matrix Metalloproteinase 3