- C-3 NOVEL TRITERPENONE WITH C-17 REVERSE AMIDE DERIVATIVES AS HIV INHIBITORS
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The present invention relates to C-3 novel triterpenone with C-17 reverse amide compounds of Formula (I); and pharmaceutically acceptable salts thereof, wherein ring Formula (II), R1, R2, R3, R4, R5, R6, R7, 'n' and 'm' are as defined in Formula (I). The invention also relates to C-3 novel triterpenone with C-17 reverse amide derivatives, related compounds, and pharmaceutical compositions useful for the therapeutic treatment of viral diseases and particularly HIV mediated diseases.
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- METHODS OF USING SEMI-SYNTHETIC GLYCOPEPTIDES AS ANTIBACTERIAL AGENTS
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Methods of using semi-synthetic glycopeptides of formula I-XIV having antibacterial activity are described.
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- Improvement of physiochemical properties of the tetrahydroazepinoindole series of farnesoid X receptor (FXR) agonists: Beneficial modulation of lipids in primates
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In an effort to develop orally active farnesoid X receptor (FXR) agonists, a series of tetrahydroazepinoindoles with appended, solubilizing amine functionalities were synthesized. The crystal structure of the previously disclosed FXR agonist, 1 (FXR-450), aided in the design of compounds with tethered solubilizing functionalities designed to reach the solvent cavity around the hFXR receptor. These compounds were soluble in 0.5% methylcellulose/2% Tween-80 in water (MC/T) for oral administration. In vitro and in vivo optimization led to the identification, of 14dd and 14cc, which in a dosedependent fashion regulated low density lipoprotein, cholesterol (LDLc) in low density lipoprotein receptor knockout (LDLR-/-) mice. Compound 14cc was dosed in female rhesus monkeys for 4 weeks at 60 mg/kg daily in MC/T vehicle. After 7 days, triglyceride (TG) levels and very low density lipoprotein cholesterol (VLDLc) levels were significantly decreased and LDLc was decreased 63%. These data are the first to demonstrate the dramatic lowering of serum LDLc levels by a FXR agonist in primates and supports the potential utility of 14cc in treating dyslipidemia in humans beyond just TG lowering.
- Lundquist IV, Joseph T.,Harnish, Douglas C.,Kim, Callain Y.,Mehlmann, John F.,Unwalla, Rayomand J.,Phipps, Kristin M.,Crawley, Matthew L.,Commons, Thomas,Green, Daniel M.,Xu, Weixin,Hum, Wah-Tung,Eta, Julius E.,Feingold, Irene,Patel, Vikram,Evans, Mark J.,Lai, Kehdih,Borges-Marcucci, Lisa,Mahaney, Paige E.,Wrobel, Jay E.
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experimental part
p. 1774 - 1787
(2010/08/06)
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- 1,2,3,6-TETRAHYDROAZEPINO[4,5-B]INDOLE-5-CARBOXYLATE NUCLEAR RECEPTOR INHIBITORS
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Provided are certain 1,2,3,6- tetrahydroazepino[4,5-b]indole-5-carboxylate compounds which are useful for modulating the activity of nuclear receptors, such as farnesoid X receptors, and/or for the treatment, prevention, or amelioration diseases or disorders related to the activity of these receptors.
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Page/Page column 59
(2010/04/27)
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- Falcipain inhibitors: Optimization studies of the 2-pyrimidinecarbonitrile lead series
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Falcipain-2 and falcipain-3 are papain-family cysteine proteases of the malaria parasite Plasmodium falciparum that are responsible for host hemoglobin hydrolysis to provide amino acids for parasite protein synthesis. Different heteroarylnitrile derivatives were studied as potential falcipain inhibitors and therefore potential antiparasitic lead compounds, with the 5-substituted-2- cyanopyrimidine chemical class emerging as the most potent and promising lead series. Through a sequential lead optimization process considering the different positions present in the initial scaffold, nanomolar and subnanomolar inhibitors at falcipains 2 and 3 were identified, with activity against cultured parasites in the micromolar range. Introduction of protonable amines within lead molecules led to marked improvements of up to 1000 times in activity against cultured parasites without noteworthy alterations in other SAR tendencies. Optimized compounds presented enzymatic activities in the picomolar to low nanomolar range and antiparasitic activities in the low nanomolar range.
- Coterón, Jose M.,Catterick, David,Castro, Julia,Chaparro, María J.,Díaz, Beatriz,Fernández, Esther,Ferrer, Santiago,Gamo, Francisco J.,Gordo, Mariola,Gut, Jiri,De Las Heras, Laura,Legac, Jennifer,Marco, Maria,Miguel, Juan,Mu?oz, Vicente,Porras, Esther,De La Rosa, Juan C.,Ruiz, Jose R.,Sandoval, Elena,Ventosa, Pilar,Rosenthal, Philip J.,Fiandor, Jose M.
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supporting information; experimental part
p. 6129 - 6152
(2010/10/21)
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- 2,4-SUBSTITUTED PYRIMIDINES AS CYSTEINE PROTEASE INHIBITORS
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Substituted heteroaryl nitrile derivatives of Formula (I) processes for their preparation, pharmaceutical compositions comprising such compounds and use of the compounds as cysteine protease inhibitors are provided.
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Page/Page column 56-57
(2010/10/20)
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- INHIBITORS OF HISTONE DEACETYLASE
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The invention relates to the inhibition of histone deacetylase. The invention provides compounds and methods for inhibiting histone deacetylase enzymatic activity. The invention also provides compositions and methods for treating cell proliferative diseases and conditions.
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Page/Page column 207-208
(2010/02/11)
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- Aromatic carboxamides
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Compounds of the general formula STR1 wherein R1 is hydrogen, halogen or OR5 ; R2 is hydrogen, lower-alkyl, lower-alkoxy or halogen; R3 and R4 each independently are lower-alkyl or taken together are alkylene with 3-5 C atoms in a straight-chain; R5 is hydrogen, acyl, lower-alkoxycarbonyl, lower-alkyl, amino-lower-alkyl, mono-alkylamino-lower-alkyl, di-alkylamino-lower-alkyl or a N-containing 5-8-membered saturated or unsaturated monocyclic heterocyclic ring which is attached via a N atom to lower alkyl; and M signifies --CONH-- or --NHCO--, which can be used as medicaments, e.g., for the treatment of neoplasms and dermatological indications of an inflammatory and allergic nature.
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