- Carbonic anhydrase and matrix metalloproteinase inhibitors. Inhibition of human tumor-associated isozymes IX and cytosolic isozyme I and II with sulfonylated hydroxamates
-
A series of sulfonylated hydroxamates were synthesized and evaluated as dual inhibitors of both human carbonic anhydrases (hCAs) and matrix metalloproteinases (MMPs), two metalloenzyme families involved in carcinogenesis and tumor invasion processes. The
- Nuti, Elisa,Orlandini, Elisabetta,Nencetti, Susanna,Rossello, Armando,Innocenti, Alessio,Scozzafava, Andrea,Supuran, Claudiu T.
-
p. 2298 - 2311
(2007/10/03)
-
- Discovery of potent, selective 4-fluoroproline-based thrombin inhibitors with improved metabolic stability
-
Previous reports from our laboratories described potent tripeptide thrombin inhibitors which incorporate heterocycle-substituted chlorophenyl groups in the P1 position. Using these as lead compounds for further optimization, we identified sites of metabolism and designed analogs with 4-fluoroproline in P2 and cyclopropane-containing side chains in P3 as an approach to reducing metabolism and improving their oral pharmacokinetic performance. The large (300-fold) difference in potency between analogs containing (4R)- and (4S)-4-fluoroproline was rationalized by analyzing inhibitor-enzyme interactions in crystal structures of related compounds and by molecular modeling which indicated that the more potent (4R)-4-fluoroproline isomer stabilizes a proline ring conformation that is preferred for binding to the enzyme. An optimal compound from this work, 41, exhibits high potency in a coagulation assay in human plasma (2×APTT = 190 nM), excellent selectivity versus the digestive enzyme trypsin (Ki = 3300 nM), and excellent oral bioavailability in dogs with moderate clearance (F = 100%, CL = 12 mL/min/kg).
- Staas, Donnette D.,Savage, Kelly L.,Sherman, Vanessa L.,Shimp, Heidi L.,Lyle, Terry A.,Tran, Lekhanh O.,Wiscount, Catherine M.,McMasters, Daniel R.,Sanderson, Philip E.J.,Williams, Peter D.,Lucas Jr., Bobby J.,Krueger, Julie A.,Dale Lewis,White, Rebecca B.,Yu, Sean,Wong, Bradley K.,Kochansky, Christopher J.,Reza Anari,Yan, Youwei,Vacca, Joseph P.
-
p. 6900 - 6916
(2007/10/03)
-
- Carbon-carbon bond construction on solid support: Triethylborane-induced radical reactions of oxime ethers
-
The triethylborane-induced solid-phase radical reaction was studied. The solid-phase radical reaction of oxime ether anchored to Wang resin proceeded smoothly to give the α-amino acid derivatives. The carbon-carbon bond-forming radical reaction of TentaGe
- Miyabe, Hideto,Nishimura, Azusa,Fujishima, Yumi,Naito, Takeaki
-
p. 1901 - 1907
(2007/10/03)
-
- Synthesis and antimicrobial properties of cephalosporin derivatives substituted on the C(7) nitrogen with arylmethyloxyimino or arylmethyloxyamino alkanoyl groups
-
Some 7-aminocephalosporanic acid (7-ACA) derivatives substituted on the C(7) nitrogen with 2-(arylmethyloxyimino)propionyl (3a-f), 2-(arylmethyloxyamino)propionyl (4a-d) and (arylmethyloxyamino)acetyl (2a-d) moieties were synthesized by reaction of the ap
- Gentili, Daniela,Macchia, Marco,Menchini, Elisabetta,Nencetti, Susanna,Orlandini, Elisabetta,Rossello, Armando,Broccali, Giampietro,Limonta, Donatella
-
p. 224 - 231
(2007/10/03)
-