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A useful and novel set of tool molecules have been identified which bind irreversibly to the JAK3 active site cysteine residue. The design was based on crystal structure information ...and a comparative study of several electrophilic warheads.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
A new class of Janus kinase (JAK) inhibitors was discovered using a rationally designed pyrrolo1,2-bpyridazine-3-carboxamide scaffold. Preliminary studies identified ...(R)-(2,2-dimethylcyclopentyl)amine as a preferred C4 substituent on the pyrrolopyridazine core (3b). Incorporation of amino group to 3-position of the cyclopentane ring resulted in a series of JAK3 inhibitors (4g-4j) that potently inhibited IFNγ production in an IL2-induced whole blood assay and displayed high functional selectivity for JAK3-JAK1 pathway relative to JAK2. Further modifications led to the discovery of an orally bioavailable (2-fluoro-2-methylcyclopentyl)amino analogue 5g which is a nanomolar inhibitor of both JAK3 and TYK2, functionally selective for the JAK3-JAK1 pathway versus JAK2, and active in a human whole blood assay.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
A series of 2,2-dimethyl-3,3-diphenyl-propanamides as novel glucocorticoid receptor modulators is reported. SAR exploration led to the identification of 4-hydroxyphenyl propanamide derivatives ...displaying good agonist activity in GR-mediated transrepression assays and reduced agonist activity in GR-mediated transactivation assays. Compounds 17 and 30 showed anti-inflammatory activity comparable to prednisolone in the rat carrageenan-induced paw edema model, with markedly decreased side effects with regard to increases in blood glucose and expression of hepatic tyrosine aminotransferase. A hypothetical binding mode accounting for the induction of the functional activity by a 4-hydroxyl group is proposed.
A series of dihydro-9,10-ethano-anthracene-11-carboxamides as novel glucocorticoid receptor modulators is reported. SAR exploration identified compounds from this series displaying a promising ...dissociation profile in discriminating between transrepression and transactivation activities.
17a is a partial agonist of GR-mediated transactivation which elicits potent and efficacious transrepression in reporter gene assays. A hypothetical binding mode is provided which accounts for the induction of functional activity by a bridgehead methyl group.
A series of dihydro-9,10-ethano-anthracene-11-carboxamides as novel glucocorticoid receptor modulators is reported. SAR exploration identified compounds from this series displaying a promising dissociation profile in discriminating between transrepression and transactivation activities.
17a is a partial agonist of GR-mediated transactivation which elicits potent and efficacious transrepression in reporter gene assays. A hypothetical binding mode is provided which accounts for the induction of functional activity by a bridgehead methyl group.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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The highly regioselective Diels–Alder reactions of 9-substituted anthracenes and 2-acetamidoacrylate afford a series of novel and conformationally constrained bicyclic bisaryl α-amino ...acids.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Modification of the cladinose C-4″ position via manipulation of the corresponding keto derivatives afforded two stereochemically pure series of compounds. The synthesis and structure determination of ...these compounds is described within. The in vitro and in vivo biological activity of this novel series of C-4″ modified macrolides is also described.
Novel C-4″ modified macrocyclic antibiotics with potent in vitro activity against
Pasteurella multocida and
Escherichia coli strains of bacteria are described.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The study of thiazoles and their derivatives has continued to flourish primarily, because of their importance as both synthetic targets and drug candidates. This chapter discusses the syntheses and ...reactions of these 5-membered heterocyclic ring systems containing nitrogen (N) and sulfur (S) or selenium (Se) or tellurium (Te). The importance of these π-rich heterocycles in medicinal chemistry and natural products is also discussed. The Hantzsch reaction discovered in 1889 remains one of the most reliable routes to thiazoles and several applications of this reaction appeared during the past year. This approach has been used twice to form both thiazole rings of the cyclopeptide dendroamide. Thiazoles can also be derived from 1, 4-dicarbonyl compounds, which are available through the N-H insertion reaction of rhodium carbenoids. Thiazoles can be prepared from thiazolines by oxidation with activated manganese dioxide. A convenient synthesis of 2-mercaptobenzothiazoles features an exclusive orthoselective nucleophilic aromatic substitution reaction of ortho-halo-anilines and subsequent intramolecular cyclization of the intermediate O-ethyl carbonodithioates. Among a variety of methods for the construction of thiazolines, the cyclodehydration protocol is perhaps most popular. In the total synthesis of cyclopeptide YM-216391, (diethylamino) sulfur trifluoride (DAST) is used as the cyclodehydrating agent for the conversion of β-hydroxy thioamide to thiazoline.
