- CARBOXY-PEPTIDYL DERIVATIVES AS ANTIDEGENERATIVE ACTIVE AGENTS
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Novel Carboxy-peptidyl compounds of Formula I are found to be useful inhibitors of matrix metalloendoproteinase-mediated diseases including osteoarthritis, rheumatoid arthritis, septic arthritis, tumor invasion in certain cancers, periodontal disease, corneal ulceration, proteinuria, dystrophobic epidermolysis bullosa, coronary thrombosis associated with atherosclerotic plaque rupture, and aneurysmal aortic disease. The matrix metalloendoproteinases are a family of zinc-containing proteinases including but not limited to stromelysin, collagenase, and gelatinase, that are capable of degrading the major components of articular cartilage and basement membranes. The inhibitors claimed herein may also be useful in preventing the pathological sequelae following a traumatic injury that could lead to a permanent disability. These compounds may also have utility as a means for birth control by preventing ovulation or implantation. STR1
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- Orally active inhibitors of stromelysin-1 (MMP-3)
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Further development of N-carboxyalkyl dipeptide inhibitors of stromelysin-1 (MMP-3) led to the discovery of C-carboxyalkyl dipeptide analogs with improved oral bioavailability. An in vivo assay of human MMP-3 mediated degradation of a macromolecular substrate in an extravascular space is described and inhibition studies are reported.
- Chapman, Kevin T.,Durette, Philippe L.,Caldwell, Charles G.,Sperow, Kelly M.,Niedzwiecki, Lisa M.,Harrison, Richard K.,Saphos, Cheryl,Christen, Amy J.,Olszewski, Julie M.,Moore, Vernon L.,MacCoss, Malcolm,Hagmann, William K.
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p. 803 - 806
(2007/10/03)
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- Structural optimization of 4-(2-chlorophenyl)-9-methyl-6H-thieno [3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepines as antagonists for platelet activating factor: Pharmacological contribution of substituents at the 2- and 6-positions of a condensed ring system
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A series of 4-(2-chlorophenyl)-9-methyl-6H-thieno [3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine derivatives bearing substituents at the 2- and 6-positions were synthesized, and evaluated in vitro for their inhibitory activity on rabbit platelet aggregation induced by platelet activating factor (PAF) and in vivo for their preventing effect on PAF-induced mortality in mice. The length of alkyl or arylalkyl side chain at the 2-position was responsible for enhancing the affinity for the PAF receptor. The simultaneous substitution at both the 2- and 6-positions resulted in a successful separation of the affinity for the PAF receptor from that for the benzodiazepine (BZ) receptor. Thus, (±)-4-(2-chlorophenyl)-2-[2-(4-isobutylphenyl)ethyl]- 6,9-dimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4] diazepine (Y-24180) was confirmed to be a specific antagonist for the PAF receptor and is currently under clinical trials.
- Kawakami,Kitani,Yuasa,Abe,Moriwaki,Kagoshima,Terasawa,Tahara
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p. 683 - 692
(2007/10/03)
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- LONG-ACTING CONTRACEPTIVE AGENTS: NORETHISTERONE ESTERS OF ARYLCARBOXYLIC ACIDS
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The synthesis of esters of norethisterone (17α-ethynyl-17β-hydroxyestr-4-en-3-one) with acids containing a benzene ring is described, two methods of esterification being compared in terms of yield and convenience.The activities of these esters as long-acting contraceptive agents have been evaluated.
- Wan, A. S. C.,Ngiam, T. L.,Leung, S. L.,Go, M. L.,Heng, P. W. S.,et al.
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p. 309 - 320
(2007/10/02)
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