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.
A new class of HCV NS3/4a protease inhibitors containing a P2 to P4 macrocyclic constraint was designed using a molecular modeling-derived strategy. Building on the profile of previous clinical ...compounds and exploring the P2 and linker regions of the series allowed for optimization of broad genotype and mutant enzyme potency, cellular activity, and rat liver exposure following oral dosing. These studies led to the identification of clinical candidate 15 (MK-5172), which is active against genotype 1–3 NS3/4a and clinically relevant mutant enzymes and has good plasma exposure and excellent liver exposure in multiple species.
Neuroimaging of the Postoperative Spine Bellini, Matteo; Ferrara, Marco; Grazzini, Irene ...
Magnetic resonance imaging clinics of North America,
08/2016, Letnik:
24, Številka:
3
Journal Article
Recenzirano
Operative treatments of the spine are becoming increasingly more common for the availability of a wide range of surgical and minimally invasive procedures. MR imaging allows for excellent evaluation ...of both normal and abnormal findings in the postoperative spine. This article provides the basic tools to evaluate complications after different operative procedures and offers an overview on the main topics a radiologist may encounter during his or her professional carrier.
Trimethylsilyldiazomethane has been found to add directly to N-sulfonyl (Ts and SES) imines to afford aziridines in good yields and high cis stereoselectivities. The silyl group can be substituted by ...treatment with a fluoride source and electrophiles again with high selectivity. Complete regioselectivity is observed in ring opening of these aziridines with nucleophiles.
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.
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