Human immunodeficiency virus type-1 (HIV-1) integrase is one of the three virally encoded enzymes required for replication and therefore a rational target for chemotherapeutic intervention in the ...treatment of HIV-1 infection. We report here the discovery of Raltegravir, the first HIV-integrase inhibitor approved by FDA for the treatment of HIV infection. It derives from the evolution of 5,6-dihydroxypyrimidine-4-carboxamides and N-methyl-4-hydroxypyrimidinone-carboxamides, which exhibited potent inhibition of the HIV-integrase catalyzed strand transfer process. Structural modifications on these molecules were made in order to maximize potency as HIV-integrase inhibitors against the wild type virus, a selection of mutants, and optimize the selectivity, pharmacokinetic, and metabolic profiles in preclinical species. The good profile of Raltegravir has enabled its progression toward the end of phase III clinical trials for the treatment of HIV-1 infection and culminated with the FDA approval as the first HIV-integrase inhibitor for the treatment of HIV-1 infection.
Solid‐phase synthesis of polyketide‐type sequences, such as 1, can be achieved efficiently by iterative, boron‐mediated, aldol reactions of chiral ketones 2 with a polystyrene‐supported aldehyde 3. ...Combinatorial variation of the chain extension units, and the stereochemistry of the aldol and reduction steps, leads to the expansion of polyketide molecular diversity. PMB=p‐MeOC6H4CH2.
The hexahydropyrimido1,2-
aazepine-2-carboxamide derivative
1 could be obtained by three synthetic strategies, which allowed access to multigram amounts of material of high purity and ee. Two ...strategies involved alternative approaches to the bicyclic pyrimidone core, with the most efficient one being a two-step sequence from commercially available starting materials exploiting a little precedented cyclisation reaction. The remaining steps to
1 included an efficient crystallisation of an intermediate as a single stereoisomer. An alternative strategy employing a chiral starting material led to products of low optical purity but allowed the assignment of the configuration of the stereogenic centre of
1.
This book investigates lifecycle management strategies used by pharmaceutical companies attempting to maximize the value of their product portfolio. Such strategies are sometimes referred to by ...generic drug companies as “evergreening”. The analysis focuses on two of these strategies, namely product improvements and product line extensions. In particular, an evaluation of the patents that follow the basic one and that accompany the development of a drug from research to market is attempted. Two “blockbuster” drugs, Taxotere and Xalatan, were randomly chosen to carry out such analysis. The patent portfolio of the originator companies is outlined and some important patents for each area of research (e.g. formulations, combinations, delivery devices) are shortly described. Patent filing trends for the two drugs, both in regards of the originator and in regards of other competing companies (amongst these also the generics) are schematically shown.
The application of a phosphoramidate prodrug approach to 2′-C-methylcytidine (NM107), the first nucleoside inhibitor of the hepatitis C virus (HCV) NS5B polymerase, is reported. 2′-C-Methylcytidine, ...as its valyl ester prodrug (NM283), was efficacious in reducing the viral load in patients infected with HCV. Several of the phosphoramidates prepared demonstrated a 10- to 200-fold superior potency with respect to the parent nucleoside in the cell-based replicon assay. This is due to higher levels of 2′-C-methylcytidine triphosphate in the cells. These prodrugs are efficiently activated and converted to the triphosphate in hepatocytes of several species. Our SAR studies ultimately led to compounds that gave high levels of NTP in hamster and rat liver after subcutaneous dosing and that were devoid of the toxic phenol moiety usually found in ProTides.
The synthesis and SAR of a new class of HIV-1 integrase inhibitors is reported.
A new class of inhibitors of HIV-1 integrase has been optimized to provide selective and highly efficient strand ...transfer inhibition.
Chronic hepatitis C virus (HCV) infections are a significant medical problem worldwide. The NS5B Polymerase of HCV plays a central role in virus replication and is a prime target for the discovery of ...new treatment options. We recently disclosed 1
H-benzo
deisoquinoline-1,3(2
H)-diones as allosteric inhibitors of NS5B Polymerase. Structural and SAR information guided us in the modification of the core structure leading to new templates with improved activity and toxicity/activity window.
HIV integrase is one of the three enzymes encoded by HIV genome and is essential for viral replication, but integrase inhibitors as marketed drugs have just very recently started to emerge. In this ...study, we show the evolution from the N-methylpyrimidinone structure to bicyclic pyrimidinones. Introduction of a suitably substituted amino moiety modulated the physical−chemical properties of the molecules and conferred nanomolar activity in the inhibition of spread of HIV-1 infection in cell culture. An extensive SAR study led to sulfamide (R)-22b, which inhibited the strand transfer with an IC50 of 7 nM and HIV infection in MT4 cells with a CIC95 of 44 nM, and ketoamide (S)-28c that inhibited strand transfer with an IC50 of 12 nM and the HIV infection in MT4 cells with a CIC95 of 13 nM and exhibited a good pharmacokinetic profile when dosed orally to preclinical species.
