L'invention porte sur des β-carbolines substituees en position 4 et des analogues de β-carbol... more L'invention porte sur des β-carbolines substituees en position 4 et des analogues de β-carbolines inhibant l'influx de Ca+2 et la production d'interleukine-2 (IL-2). Les β-carbolines substituees en position 4 et les analogues de β-carbolines objets de l'invention sont representes par la formule (I) dans laquelle Q, n, R, R', R'' et R?1?-R4 sont tels que definis dans la description. L'invention porte egalement sur des procedes de production des β-carbolines. En raison de leurs proprietes immunomodulatrices, les composes et preparations pharmaceutiques de l'invention sont particulierement bien adaptes a la prevention et au traitement de troubles du systeme immunitaire, dont les maladies auto-immunes, les maladies inflammatoires, le rejet des organes transplantes, et autres troubles associes a la reponse immunitaire induite par l'IL-2.
A novel class of lymphocyte function-associated antigen-1 (LFA-1) inhibitors is described. Discov... more A novel class of lymphocyte function-associated antigen-1 (LFA-1) inhibitors is described. Discovered during the process to improve the physicochemical and metabolic properties of BIRT377 (1, Figure 1), a previously reported hydantoin-based LFA-1 inhibitor, these compounds are characterized by an imidazole-based 5,5-bicyclic scaffold, the 1,3,3-trisubstituted 1Himidazo[1,2-R]imidazol-2-one (i.e. structure 3). The structure-activity relationship (SAR) shows that electron-withdrawing groups at C 5 on the imidazole ring benefit potency and that oxygencontaining functional groups attached to a C 5-sulfonyl or sulfonamide group further improve potency. This latter gain in potency is attributed to the interaction(s) of the functionalized sulfonyl/sulfonamide groups with the protein, likely polar-polar in nature, as suggested by SAR data. X-ray studies revealed that these bicyclic inhibitors bind to the I-domain of LFA-1 in a pattern similar to that of compound 1.
A novel dipyridodiazepinone, 6,ll-dihydro-1 1-cyclopropyl-4-methyldipyrido[2,3-b:2',3'-e]-[ 1,4]d... more A novel dipyridodiazepinone, 6,ll-dihydro-1 1-cyclopropyl-4-methyldipyrido[2,3-b:2',3'-e]-[ 1,4]diazepin-6-one (BI-RG-587), is a selective noncompetitive inhibitor of HIV-1 reverse transcriptase (RT-1). An azido photoaffinity analogue of BI-RG-587 was synthesized and found to irreversibly inhibit the enzyme upon UV irradiation. BI-RG-587 and close structural analogues competitively protected RT-1 from inactivation by the photoaffinity label. A thiobenzimidazolone (TIBO) derivative, a nonnucleoside inhibitor of RT-1, also protected the enzyme from photoinactivation, which suggests a common binding site for these compounds. Substrates dGTP, template-primer, and tRNA afforded no protection from enzyme inactivation. A tritiated photoaffinity probe was found to stoichiometrically and selectively label p66 such that 1 mol of probe inactivates 1 mol of RT-1. x e transcription of viral RNA to proviral DNA by the enzyme reverse transcriptase (RT-I)' is a requisite step in the life cycle of human immunodeficiency virus 1 (HIV-1) (Fauci, 1988). Progress has been made in the development of chemotherapeutic agents such as the nucleoside analogue 3'
Meloxicam (5), an NSAID in the enol-carboxamide class, was developed on the basis of its antiinfl... more Meloxicam (5), an NSAID in the enol-carboxamide class, was developed on the basis of its antiinflammatory activity and relative safety in animal models. In subsequent screening in microsomal assays using human COX-1 and COX-2, we discovered that it possessed a selectivity profile for COX-2 superior to piroxicam and other marketed NSAIDs. We therefore embarked on a study of enol-carboxamide type compounds to determine if COX-2 selectivity and potency could be dramatically improved by structural modification. Substitution at the 6-and 7-positions of the 4-oxo-1,2-benzothiazine-3-carboxamide, alteration of the N-methyl substituent, and amide modification were all examined. In addition we explored several related systems including the isomeric 3-oxo-1,2-benzothiazine-4-carboxamides, thienothiazines, indolothiazines, benzothienothiazines, naphthothiazines, and 1,3-and 1,4-dioxoisoquinolines. While a few examples were found with greater potency in the COX-2 assay, no compound tested had a better COX-2/COX-1 selectivity profile than that of 5.
L'invention porte sur des β-carbolines substituees en position 4 et des analogues de β-carbol... more L'invention porte sur des β-carbolines substituees en position 4 et des analogues de β-carbolines inhibant l'influx de Ca+2 et la production d'interleukine-2 (IL-2). Les β-carbolines substituees en position 4 et les analogues de β-carbolines objets de l'invention sont representes par la formule (I) dans laquelle Q, n, R, R', R'' et R?1?-R4 sont tels que definis dans la description. L'invention porte egalement sur des procedes de production des β-carbolines. En raison de leurs proprietes immunomodulatrices, les composes et preparations pharmaceutiques de l'invention sont particulierement bien adaptes a la prevention et au traitement de troubles du systeme immunitaire, dont les maladies auto-immunes, les maladies inflammatoires, le rejet des organes transplantes, et autres troubles associes a la reponse immunitaire induite par l'IL-2.
A novel class of lymphocyte function-associated antigen-1 (LFA-1) inhibitors is described. Discov... more A novel class of lymphocyte function-associated antigen-1 (LFA-1) inhibitors is described. Discovered during the process to improve the physicochemical and metabolic properties of BIRT377 (1, Figure 1), a previously reported hydantoin-based LFA-1 inhibitor, these compounds are characterized by an imidazole-based 5,5-bicyclic scaffold, the 1,3,3-trisubstituted 1Himidazo[1,2-R]imidazol-2-one (i.e. structure 3). The structure-activity relationship (SAR) shows that electron-withdrawing groups at C 5 on the imidazole ring benefit potency and that oxygencontaining functional groups attached to a C 5-sulfonyl or sulfonamide group further improve potency. This latter gain in potency is attributed to the interaction(s) of the functionalized sulfonyl/sulfonamide groups with the protein, likely polar-polar in nature, as suggested by SAR data. X-ray studies revealed that these bicyclic inhibitors bind to the I-domain of LFA-1 in a pattern similar to that of compound 1.
A novel dipyridodiazepinone, 6,ll-dihydro-1 1-cyclopropyl-4-methyldipyrido[2,3-b:2',3'-e]-[ 1,4]d... more A novel dipyridodiazepinone, 6,ll-dihydro-1 1-cyclopropyl-4-methyldipyrido[2,3-b:2',3'-e]-[ 1,4]diazepin-6-one (BI-RG-587), is a selective noncompetitive inhibitor of HIV-1 reverse transcriptase (RT-1). An azido photoaffinity analogue of BI-RG-587 was synthesized and found to irreversibly inhibit the enzyme upon UV irradiation. BI-RG-587 and close structural analogues competitively protected RT-1 from inactivation by the photoaffinity label. A thiobenzimidazolone (TIBO) derivative, a nonnucleoside inhibitor of RT-1, also protected the enzyme from photoinactivation, which suggests a common binding site for these compounds. Substrates dGTP, template-primer, and tRNA afforded no protection from enzyme inactivation. A tritiated photoaffinity probe was found to stoichiometrically and selectively label p66 such that 1 mol of probe inactivates 1 mol of RT-1. x e transcription of viral RNA to proviral DNA by the enzyme reverse transcriptase (RT-I)' is a requisite step in the life cycle of human immunodeficiency virus 1 (HIV-1) (Fauci, 1988). Progress has been made in the development of chemotherapeutic agents such as the nucleoside analogue 3'
Meloxicam (5), an NSAID in the enol-carboxamide class, was developed on the basis of its antiinfl... more Meloxicam (5), an NSAID in the enol-carboxamide class, was developed on the basis of its antiinflammatory activity and relative safety in animal models. In subsequent screening in microsomal assays using human COX-1 and COX-2, we discovered that it possessed a selectivity profile for COX-2 superior to piroxicam and other marketed NSAIDs. We therefore embarked on a study of enol-carboxamide type compounds to determine if COX-2 selectivity and potency could be dramatically improved by structural modification. Substitution at the 6-and 7-positions of the 4-oxo-1,2-benzothiazine-3-carboxamide, alteration of the N-methyl substituent, and amide modification were all examined. In addition we explored several related systems including the isomeric 3-oxo-1,2-benzothiazine-4-carboxamides, thienothiazines, indolothiazines, benzothienothiazines, naphthothiazines, and 1,3-and 1,4-dioxoisoquinolines. While a few examples were found with greater potency in the COX-2 assay, no compound tested had a better COX-2/COX-1 selectivity profile than that of 5.
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Papers by Ian Potocki