BMS-200475, a novel carbocyclic analog of 2′-deoxyguanosine, is a potent inhibitor of hepatitis B virus in vitro (ED
50 = 3 nM) with relatively low cytotoxicity (CC
50 = 21–120 μM). A practical ...10-step asymmetric synthesis was developed affording BMS-200475 in 18% overall chemical yield and >99% optical purity. The enantiomer of BMS-200475 as well as the adenine, thymine, and iodouracil analogs are much less active.
BMS-200475, a novel carbocyclic analog of 2′-deoxyguanosine, is a potent inhibitor of hepatitis B virus in vitro (ED
50 = 3nM) with relatively low cytotoxicity (CC
50 = 21–120 μM).
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IJS, IMTLJ, KILJ, KISLJ, NUK, SBCE, SBJE, UL, UM, UPCLJ, UPUK
A library of compounds were prepared by reacting 2-(bromomethyl)-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (5) with commercially available carboxylic acids in the presence of potassium carbonate or a ...tertiary amine base. From this library, (1,1-dioxido-3-oxo-1,2-benzisothiazol-2(3H)-yl)methyl N-(phenylmethoxy)carbonyl-β-alanate (7b) emerged as a potent inhibitor of human mast cell tryptase (IC50 = 0.85 μM). Extension of the side chain of 7b by two carbons gave (1,1-dioxido-3-oxo-1,2-benzisothiazol-2(3H)-yl)methyl 5-(phenylmethoxy)carbonylaminopentanoate (7d) which was an 8-fold more potent inhibitor (IC50 = 0.1 μM). Further modification of this series produced benzoic acid derivative (1,1-dioxido-3-oxo-1,2-benzisothiazol-2(3H)-yl)methyl 4-(phenylmethoxy)carbonylaminobenzoate (7n) which is the most potent inhibitor identified in this series (IC50 = 0.064 μM). These compounds exhibit time-dependent inhibition consistent with mechanism-based inhibition. For 7b, the initial enzyme velocity is not a saturable function of the inhibitor concentration and the initial K i could not be determined (K i > 10 μM). The steady-state rate constant, K i*, was determined to be 396 nM. On the other hand, compounds 7d and 7n are time-dependent inhibitors with a saturable initial complex. From these studies, an initial rate constant, K i, for 7d and 7n was found to be 345 and 465 nM, respectively. The steady-state inhibition constants, K i*, for 7d and 7n were calculated to be 60 and 52 nM, respectively. Compound 7n is a 13-fold more potent inhibitor than 7b, and these kinetic studies indicate that the increase in inhibitory activity is due to an increase in initial affinity toward the enzyme and not an increase in chemical reactivity. These inhibitors generally show high selectivity for tryptase, being 40-fold weaker inhibitors of elastase, being 100-fold weaker against trypsin, and showing no inhibition against thrombin. These compounds are not inhibitors of thrombin, plasmin t-PA, urokinase, and factor Xa (IC50 > 33 μM). In the delayed-type hypersensitivity (DTH) mouse model, a model of skin inflammation, a 5% solution of 7d reduced edema by 69% compared to control animals.
A series of nonguanidine N1-activated C4-carboxy azetidinone tryptase inhibitors was prepared by solid-phase methodology to quickly assess the SAR associated with distal functionality on the ...N1-activating group. From these studies, potent inhibitors with improved specificity were discovered.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Azetidinones such as BMS-363131 (2) and BMS-363130 (3), which contain a guanidine group in the C-3 side chain were previously shown to be very potent inhibitors of human tryptase with high ...selectivity versus other serine proteases, including trypsin. In this letter, we describe the discovery of a number of potent azetidinone tryptase inhibitors in which the guanidine moiety at the ring C-3 position is replaced with primary or secondary amine or aminopyridine functionality. In particular, BMS-354326 (4) is a highly potent tryptase inhibitor (IC(50)=1.8 nM), which has excellent selectivity against trypsin and most other related serine proteases.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
A series of N1-activated C4-carboxy azetidinones was prepared and tested as inhibitors of human tryptase. The key stereochemical and functional features required for potency, serine protease ...specificity and aqueous stability were determined. From these studies compound
2, BMS-262084, was identified as a potent and selective tryptase inhibitor which, when dosed intratracheally in ovalbumin-sensitized guinea pigs, reduced allergen-induced bronchoconstriction and inflammatory cell infiltration into the lung.
BMS-262084 was identified as a potent and selective tryptase inhibitor that, when dosed intratracheally in ovalbumin-sensitized guinea pigs, reduced allergen-induced bronchoconstriction and inflammatory cell infiltration into the lung.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The serine protease tryptase has been implicated in allergic and inflammatory diseases and associated with asthma. The synthesis and SAR of a series of N1-activated-4-carboxy azetidinones are ...described, resulting in identification of BMS-363131 (
2) as a potent inhibitor of human tryptase (IC
50<1.7 nM) with high selectivity (>3000-fold) for tryptase versus related serine proteases including trypsin.
The synthesis and SAR of a series of azetidinones are described resulting in identification of BMS-363131 as a potent inhibitor of human tryptase with high selectivity for tryptase versus related serine proteases including trypsin.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The syntheses of the enantiomeric cyclobutyl guanine nucleoside analogues 1R-1 alpha, 2 beta, 3 alpha- and 1S-1 alpha, 2 beta, 3 alpha-2- amino-9-2,3-bis(hydroxymethyl)cyclobutyl-6H-purin-6-one (7 ...and 8, respectively) and the enantiomeric cyclobutyl adenine analogues 1R-1 alpha, 2 beta, 3 alpha- and 1S-1 alpha, 2 beta, 3 alpha-6-amino-9-2,3-bis(hydroxymethyl) cyclobutylpurine (9 and 10, respectively) are described. trans-3,3-Diethoxy-1,2-cyclobutanedicarboxylic acid (14) was coupled with R-(-)-2-phenylglycinol to provide a mixture of diastereomeric bis-amides, 15a and 15b, which was readily separated by crystallization. Conversion of each bis-amide to the corresponding diol enantiomer, 16a and 16b, respectively, was effected by a facile three-step sequence in high overall yield. Homochiral diol 16a was converted in a straightforward manner to 7 and 9, and homochiral diol 16b was similarly converted to the corresponding optical isomers 8 and 10. Compounds 7 and 9, which mimic the absolute configuration of natural nucleosides, are highly active against a range of herpesviruses in vitro while the isomers of opposite configuration, 8 and 10, are devoid of antiherpes activity. The corresponding triphosphates of 7 and 8 (7-TP and 8-TP) were prepared enzymatically. Compound 7-TP selectively inhibits HSV-1 DNA polymerase, compared to human (HeLa) DNA polymerase, while 8-TP is much less inhibitory than 7-TP against both types of enzymes. Compounds 7 and 9 are efficacious in a mouse cytomegalovirus model infection.
N,
N′-Disubstituted ketene aminals are good bioisosteres of thiourea functional groups. We report the design and synthesis of a novel class of ketene aminal-based lactam derivatives as potent and ...orally active FXa inhibitors.
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