Potent, selective spiropyrrolidine pyrimidinetrione inhibitors of MMP-13.
Explorations in the pyrimidinetrione series of MMP-13 inhibitors led to the discovery of a series of spiro-fused compounds that are potent and selective inhibitors of MMP-13. While other spiro-fused motifs are hydrolytically unstable, presumably due to electronic destabilization of the pyrimidinetrione ring, the spiropyrrolidine series does not share this liability. Greater than 100-fold selectivity versus other MMP family members was achieved by incorporation of an extended aryl-heteroaryl P1'group. When dosed as the sodium salt, these compounds displayed excellent oral absorption and pharmacokinetic properties. Despite the selectivity, a representative of this series produced fibroplasia in a 14 day rat study.
Freeman-Cook
Kevin D
KD
Pfizer Global Research & Development, Groton Laboratories, Eastern Point Road, Groton, CT 06340, USA. Kevin.Freeman-cook@pfizer.com
Reiter
Lawrence A
LA
Noe
Mark C
MC
Antipas
Amy S
AS
Danley
Dennis E
DE
Datta
Kaushik
K
Downs
James T
JT
Eisenbeis
Shane
S
Eskra
James D
JD
Garmene
David J
DJ
Greer
Elaine M
EM
Griffiths
Richard J
RJ
Guzman
Roberto
R
Hardink
Joel R
JR
Janat
Fouad
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Jones
Christopher S
CS
Martinelli
Gary J
GJ
Mitchell
Peter G
PG
Laird
Ellen R
ER
Liras
Jennifer L
JL
Lopresti-Morrow
Lori L
LL
Pandit
Jayvardhan
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Reilly
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Robertson
Donald
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D000818:Animals; D004795:Enzyme Stability / Q000187:drug effects; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology; D011759:Pyrrolidines / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D013141:Spiro Compounds / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D011743:Pyrimidines; D011759:Pyrrolidines; D013141:Spiro Compounds; D053509:Matrix Metalloproteinase 13