La presente invention concerne des phosphoramidates d'aryle nucleosidiques de formule structu... more La presente invention concerne des phosphoramidates d'aryle nucleosidiques de formule structurelle (I), qui sont des precurseurs d'inhibiteurs de polymerase virale d'ARN ARN dependante. Ces composes sont des precurseurs d'inhibiteurs de la replication virale d'ARN ARN dependante, et sont utiles dans le traitement d'une infection virale d'ARN ARN dependante. Ils sont particulierement utiles en tant que precurseurs d'inhibiteurs de la polymerase NS5B du virus de l'hepatite C (VHC), en tant que precurseurs d'inhibiteurs de la replication du VHC, et/ou pour le traitement de l'infection par l'hepatite C. L'invention decrit egalement des compositions pharmaceutiques contenant de tels phosphoramidates d'aryle nucleosidiques seuls ou en combinaison avec d'autres agents actifs, contre une infection virale d'ARN ARN dependante, en particulier une infection par le VHC. L'invention concerne egalement des procedes d'inhibiti...
L'invention a trait a des composes d'indole et d'azaindole representes par la formule... more L'invention a trait a des composes d'indole et d'azaindole representes par la formule (I), dans laquelle X1, X2, X3, X4, A1, Ar1, R1, R2 et n sont tels que definis dans la demande, et a des sels pharmaceutiquement acceptables de ceux-ci, utiles dans la prevention et le traitement d'infections par le virus de l'hepatite C.
Inverse agonists of the nuclear receptor RORC2 have been widely pursued as a potential treatment ... more Inverse agonists of the nuclear receptor RORC2 have been widely pursued as a potential treatment for a variety of autoimmune diseases. We have discovered a novel series of isoindoline-based inverse agonists of the nuclear receptor RORC2, derived from our recently disclosed RORC2 inverse agonist 2. Extensive structure-activity relationship (SAR) studies resulted in AZD0284 (20), which combined potent inhibition of IL-17A secretion from primary human TH17 cells with excellent metabolic stability and good PK in preclinical species. In two preclinical in vivo studies, compound 20 reduced thymocyte numbers in mice and showed dose-dependent reduction of IL-17A containing γδ-T cells and of IL-17A and IL-22 RNA in the imiquimod induced inflammation model. Based on these data and a favorable safety profile, 20 was progressed to phase 1 clinical studies.
An increasing focus on complex biology to cure diseases rather than merely treat symptoms is tran... more An increasing focus on complex biology to cure diseases rather than merely treat symptoms is transforming how drug discovery can be approached, and expands the arsenal of drug modalities and modes-of-actions that can be leveraged to modify diseases.
Retinoic acid receptor related orphan receptor γt (RORγt), has been identified as the master regu... more Retinoic acid receptor related orphan receptor γt (RORγt), has been identified as the master regulator of TH17-cell function and development, making it an attractive target for the treatment of autoimmune diseases by a small-molecule approach. Herein, we describe our investigations on a series of 4-aryl-thienyl acetamides, which were guided by insights from X-ray cocrystal structures. Efforts in targeting the cofactor-recruitment site from the 4-aryl group on the thiophene led to a series of potent binders with nanomolar activity in a primary human-TH17-cell assay. The observation of a DMSO molecule binding in a subpocket outside the LBD inspired the introduction of an acetamide into the benzylic position of these compounds. Hereby, a hydrogen-bond interaction of the introduced acetamide oxygen with the backbone amide of Glu379 was established. This greatly enhanced the cellular activity of previously weakly cell-active compounds. The best compounds combined potent inhibition of IL-17 release with favorable PK in rodents, with compound 32 representing a promising starting point for future investigations.
Nitric oxide (NO·) is a messenger molecule with diverse physiological roles including host defens... more Nitric oxide (NO·) is a messenger molecule with diverse physiological roles including host defense, neurotransmission and vascular function. The synthesis of NO· from l-arginine is catalyzed by NO-synthases and occurs in two steps through the intermediary N-hydroxy-l-arginine (NHA). In both steps the P450-like reaction cycle is coupled with the redox cycle of the cofactor tetrahydrobiopterin (HB). The mechanism of the second step is studied by Density Functional Theory calculations to ascertain the canonical sequence of proton and electron transfer (PT and ET) events. The proposed mechanism is controlled by the interplay of two electron donors, HB and NHA. Consistent with experimental data, the catalytic cycle proceeds through the ferric-hydroperoxide complex (Cpd 0) and the following aqua-ferriheme resting state, and involves interim partial oxidation of HB. The mechanism starts with formation of Cpd 0 from the ferrous-dioxy reactant complex by PT from the C-ring heme propionate co...
In an industry focused on reducing attrition, lead generation represents a critical stage in drug... more In an industry focused on reducing attrition, lead generation represents a critical stage in drug discovery wherein a considered choice of lead series can significantly reduce the time and resources committed to unpromising chemical series. To aid identification and selection of series with a specific mechanism of action, within property space suitable for the intended mode of administration, many modalities are brought into play and are discussed in this chapter. Aspects covered include the approaches used to find chemical start points, as well as some of the blind alleys that the investigator should avoid, and the need to consider lead-like properties in context of a line-of-sight to the final drug candidate. By way of help, examples are given of both successful and unsuccessful lead generation.
Microbial lipids play an important role in the formation of geologically derived organic matter1.... more Microbial lipids play an important role in the formation of geologically derived organic matter1. Among these lipids the hopanoids have a key function as they show an almost ubiquitous occurrence in sediments and fossil fuels2. In this report we have obtained bacteriohopanetetrol, the well-known presumptive precursor of most fossil hopanoids, by catalytic hydrogenolysis of the Messel oil shale kerogen (Eocene, 50 x 106 yr). The existence of chemically bonded biohopanoids in an Eocene kerogen supports the idea of incorporation of intact biological structures into high molecular weight organic matter of geological origin. Selective chemical degradation is, therefore, a valuable tool in the structural characterization of polymeric organic matter in the sedimentary environment.
La presente invention concerne des phosphoramidates d'aryle nucleosidiques de formule structu... more La presente invention concerne des phosphoramidates d'aryle nucleosidiques de formule structurelle (I), qui sont des precurseurs d'inhibiteurs de polymerase virale d'ARN ARN dependante. Ces composes sont des precurseurs d'inhibiteurs de la replication virale d'ARN ARN dependante, et sont utiles dans le traitement d'une infection virale d'ARN ARN dependante. Ils sont particulierement utiles en tant que precurseurs d'inhibiteurs de la polymerase NS5B du virus de l'hepatite C (VHC), en tant que precurseurs d'inhibiteurs de la replication du VHC, et/ou pour le traitement de l'infection par l'hepatite C. L'invention decrit egalement des compositions pharmaceutiques contenant de tels phosphoramidates d'aryle nucleosidiques seuls ou en combinaison avec d'autres agents actifs, contre une infection virale d'ARN ARN dependante, en particulier une infection par le VHC. L'invention concerne egalement des procedes d'inhibiti...
L'invention a trait a des composes d'indole et d'azaindole representes par la formule... more L'invention a trait a des composes d'indole et d'azaindole representes par la formule (I), dans laquelle X1, X2, X3, X4, A1, Ar1, R1, R2 et n sont tels que definis dans la demande, et a des sels pharmaceutiquement acceptables de ceux-ci, utiles dans la prevention et le traitement d'infections par le virus de l'hepatite C.
Inverse agonists of the nuclear receptor RORC2 have been widely pursued as a potential treatment ... more Inverse agonists of the nuclear receptor RORC2 have been widely pursued as a potential treatment for a variety of autoimmune diseases. We have discovered a novel series of isoindoline-based inverse agonists of the nuclear receptor RORC2, derived from our recently disclosed RORC2 inverse agonist 2. Extensive structure-activity relationship (SAR) studies resulted in AZD0284 (20), which combined potent inhibition of IL-17A secretion from primary human TH17 cells with excellent metabolic stability and good PK in preclinical species. In two preclinical in vivo studies, compound 20 reduced thymocyte numbers in mice and showed dose-dependent reduction of IL-17A containing γδ-T cells and of IL-17A and IL-22 RNA in the imiquimod induced inflammation model. Based on these data and a favorable safety profile, 20 was progressed to phase 1 clinical studies.
An increasing focus on complex biology to cure diseases rather than merely treat symptoms is tran... more An increasing focus on complex biology to cure diseases rather than merely treat symptoms is transforming how drug discovery can be approached, and expands the arsenal of drug modalities and modes-of-actions that can be leveraged to modify diseases.
Retinoic acid receptor related orphan receptor γt (RORγt), has been identified as the master regu... more Retinoic acid receptor related orphan receptor γt (RORγt), has been identified as the master regulator of TH17-cell function and development, making it an attractive target for the treatment of autoimmune diseases by a small-molecule approach. Herein, we describe our investigations on a series of 4-aryl-thienyl acetamides, which were guided by insights from X-ray cocrystal structures. Efforts in targeting the cofactor-recruitment site from the 4-aryl group on the thiophene led to a series of potent binders with nanomolar activity in a primary human-TH17-cell assay. The observation of a DMSO molecule binding in a subpocket outside the LBD inspired the introduction of an acetamide into the benzylic position of these compounds. Hereby, a hydrogen-bond interaction of the introduced acetamide oxygen with the backbone amide of Glu379 was established. This greatly enhanced the cellular activity of previously weakly cell-active compounds. The best compounds combined potent inhibition of IL-17 release with favorable PK in rodents, with compound 32 representing a promising starting point for future investigations.
Nitric oxide (NO·) is a messenger molecule with diverse physiological roles including host defens... more Nitric oxide (NO·) is a messenger molecule with diverse physiological roles including host defense, neurotransmission and vascular function. The synthesis of NO· from l-arginine is catalyzed by NO-synthases and occurs in two steps through the intermediary N-hydroxy-l-arginine (NHA). In both steps the P450-like reaction cycle is coupled with the redox cycle of the cofactor tetrahydrobiopterin (HB). The mechanism of the second step is studied by Density Functional Theory calculations to ascertain the canonical sequence of proton and electron transfer (PT and ET) events. The proposed mechanism is controlled by the interplay of two electron donors, HB and NHA. Consistent with experimental data, the catalytic cycle proceeds through the ferric-hydroperoxide complex (Cpd 0) and the following aqua-ferriheme resting state, and involves interim partial oxidation of HB. The mechanism starts with formation of Cpd 0 from the ferrous-dioxy reactant complex by PT from the C-ring heme propionate co...
In an industry focused on reducing attrition, lead generation represents a critical stage in drug... more In an industry focused on reducing attrition, lead generation represents a critical stage in drug discovery wherein a considered choice of lead series can significantly reduce the time and resources committed to unpromising chemical series. To aid identification and selection of series with a specific mechanism of action, within property space suitable for the intended mode of administration, many modalities are brought into play and are discussed in this chapter. Aspects covered include the approaches used to find chemical start points, as well as some of the blind alleys that the investigator should avoid, and the need to consider lead-like properties in context of a line-of-sight to the final drug candidate. By way of help, examples are given of both successful and unsuccessful lead generation.
Microbial lipids play an important role in the formation of geologically derived organic matter1.... more Microbial lipids play an important role in the formation of geologically derived organic matter1. Among these lipids the hopanoids have a key function as they show an almost ubiquitous occurrence in sediments and fossil fuels2. In this report we have obtained bacteriohopanetetrol, the well-known presumptive precursor of most fossil hopanoids, by catalytic hydrogenolysis of the Messel oil shale kerogen (Eocene, 50 x 106 yr). The existence of chemically bonded biohopanoids in an Eocene kerogen supports the idea of incorporation of intact biological structures into high molecular weight organic matter of geological origin. Selective chemical degradation is, therefore, a valuable tool in the structural characterization of polymeric organic matter in the sedimentary environment.
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