- INHIBITORS OF CYSTEINE PROTEASES AND METHODS OF USE THEREOF
-
The present invention relates to semicarbazone or thiosemicarbazone inhibitors of cysteine proteases and methods of using such compounds to prevent and treat protozoan infections such as trypanosomiasis, malaria and leishmaniasis. The compounds also find use in inhibiting cysteine proteases associated with carcinogenesis, including cathepsins B and L.
- -
-
Page/Page column 18
(2009/04/24)
-
- Design, synthesis, and biochemical evaluation of novel cruzain inhibitors with potential application in the treatment of Chagas' disease
-
A series of compounds bearing tetrahydronaphthalene, benzophenone, propiophenone, and related rigid molecular skeletons functionalized with thiosemicarbazone or unsaturated carbonyl moieties were prepared by chemical synthesis and evaluated for their ability to inhibit the enzyme cruzain. As potential treatment agents for Chagas' disease, three compounds from the group demonstrate potent inhibition of cruzain with IC50 values of 17, 24, and 80 nM, respectively.
- Siles, Rogelio,Chen, Shen-En,Zhou, Ming,Pinney, Kevin G.,Trawick, Mary Lynn
-
p. 4405 - 4409
(2007/10/03)
-
- Novel vitamin D analogs
-
Novel vitamin D analogs, markedly active in the fields of cell proliferation and differentiation, are selected from among (4E,6E)-7-{3-[2-(3,4-bis-hydroxymethylphenyl)-ethyl] phenyl}-3-ethylnona-4, 6-dien-3-ol, (E)-6-[3-(3,4-bis-hydroxymethylbenzyloxy)phe
- -
-
Page/Page column 6
(2010/02/09)
-
- CYCLOALKANE DERIVATIVES
-
The invention concerns cycloalkane derivatives of the formula I wherein Ar1 is phenyl, naphthyl or a 10-membered bicyclic heterocyclic moiety which may optionally bear up to four substituents; A1 is a direct link to X1 or is (1-3C)alkylene; X1 is oxy, thi
- -
-
-
- Heterocyclic thiazole derivatives and pharmaceutical compositions comprising said derivatives
-
The invention concerns a thiazole of the formula I, STR1 wherein Q1 is an optionally substituted 6-membered monocyclic or 10-membered bicyclic heterocyclic moiety containing one or two nitrogen atoms; X is oxy, thio, sulphinyl, sulphonyl or imino; Ar is phenylene which may optionally bear one or two substituents, or Ar is an optionally substituted 6-membered heterocyclene moiety continuing up to three nitrogen atoms; R1 is hydrogen, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl or substituted (1-4C)alkyl; R2 is hydrogen, (1-6C)alkyl, (3-6C)alkenyl, (3-6C)alkynyl or substituted (1-4C)alkyl or R2 is optionally substituted benzoyl; and Q2 is optionally substituted thiazolyl; or a pharmaceutically-acceptable salt thereof. The invention also concerns processes for the manufacture of a thiazole of the formula I and pharmaceutical compositions containing said thiazole.
- -
-
-
- 5-LIPOXYGENASE INHIBITORY THIAZOLES
-
The invention concerns a thiazole of the formula I, wherein Ar1 is optionally substituted aryl of up to 10 carbon atoms; A is a direct link to X, or is (1-6C)alkylene, (3-6C)alkenylene, (3-6C)alkynylene or cyclo(3-6C)alkylene; X is oxy, thio, sulphinyl, sulphonyl or imino; Ar2 is optionally substituted phenylene, or a 6-membered heterocyclene moiety containing up to three nitrogen atoms; R1 is hydrogen, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl or substituted (1-4C)alkyl; R2 is hydrogen, (1-6C)alkyl, (3-6C)alkenyl, (3-6C)alkynyl, substituted (1-4C)alkyl or (2-6C)alkanoyl; Q is optionally substituted thiazolyl; or a pharmaceutically-acceptable salt thereof. The invention also concerns processes for the manufacture of a thiazole of the formula I, or a pharmaceutically-acceptable salt thereof, and pharmaceutical compositions containing said thiazole
- -
-
-
- (Methoxyalkyl)thiazoles: A new series of potent, selective, and orally active 5-lipoxygenase inhibitors displaying high enantioselectivity
-
(Methoxyalkyl)thiazoles are novel 5-lipoxygenase (5-LPO) inhibitors that are neither redox agents nor iron chelators. Consideration of a hypothetical model of the enzyme active site led to this series which is exemplified by 1-[3(naphth-2-ylmethoxy)phenyl]-1-(thiazol-2-yl)propyl methyl ether (2d, ICI211965). 2d inhibits cell-free guinea pig 5-LPO activity, LTC4 synthesis in plasma free mouse macrophages, and LTB4 synthesis in rat and human blood (IC50s 0.1 μM, 8nM, 0.5 μM, and 0.4 μM, respectively) but does not inhibit the synthesis of cyclooxygenase products at concentrations up to 50 μM in macrophages and 100 μM in blood. 2d is orally active in rat (ex vivo ED50 10 mg/kg in blood taken in 1h after dosing). SAR studies show that high in vitro potency requires methoxy, thiazolyl, and naphthyl groups and depends critically on the substitution pattern. (Methoxyalkyl)thiazoles are chiral. Resolution of 1-methoxy-6-(naphth-2-ylmethoxy)-1-(thiazol-2-yl)indan (2j, ICl216800) shows that (+)-2j is 50-150-fold more potent than (-)-2j in in vitro assays. Thus, (methoxyalkyl)thiazoles are a new series of orally active, selective 5-LPO inhibitors and represent the first class of inhibitors in which inhibition is mediated by specific, enantioselective interactions with the enzyme.
- Bird,Bruneau,Crawley,Edwards,Foster,Girodeau,Kingston,McMillan
-
p. 2176 - 2186
(2007/10/02)
-
- Heterocyclic derivatives
-
The invention concerns a thiazole of the formula I, wherein Q1 is an optionally substituted 6-membered monocyclic or 10-membered bicyclic heterocyclic moiety containing one or two nitrogen atoms;, X is oxy, thio, sulphinyl, sulphonyl or imino;, Ar is phenylene which may optionally bear one or two substituents, or Ar is an optionally substituted 6-membered heterocyclene moiety contining up to three nitrogen atoms;, R1 is hydrogen, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl or substituted (1-4C)alkyl;, R2 is hydrogen, (1-6C)alkyl, (3-6C)alkenyl, (3-6C)alkynyl or substituted (1-4C)alkyl or R2 is optionally substituted benzoyl; and, Q2 is optionally substituted thiazolyl;, or a pharmaceutically-acceptable salt thereof. The invention also concerns processes for the manufacture of a thiazole of the formula I and pharmaceutical compositions containing said thiazole.
- -
-
-