1064707-10-3Relevant academic research and scientific papers
A polar radical pair pathway to assemble the pyrimidinone core of the HIV integrase inhibitor raltegravir potassium
Pye, Philip J.,Zhong, Yong-Li,Jones, Gavin O.,Reamer, Robert A.,Houk, Kendall N.,Askin, David
supporting information; experimental part, p. 4134 - 4136 (2009/03/12)
(Chemical Equation Presented) Break up to make up: Combined experimental and computational studies provide evidence that the key step in the synthesis of a novel anti-HIV drug involves an unprecedented stepwise radical pair rearrangement mechanism in which radical fragments are held together by strong electrostatic forces (see scheme); this is favored over alternative mechanisms involving concerted pericyclic rearrangement.
Discovery of raltegravir, a potent, selective orally bioavailable HIV-integrase inhibitor for the treatment of HIV-AIDS infection
Summa, Vincenzo,Petrocchi, Alessia,Bonelli, Fabio,Crescenzi, Benedetta,Donghi, Monica,Ferrara, Marco,Fiore, Fabrizio,Gardelli, Cristina,Paz, Odalys Gonzalez,Hazuda, Daria J.,Jones, Philip,Kinzel, Olaf,Laufer, Ralph,Monteagudo, Edith,Muraglia, Ester,Nizi, Emanuela,Orvieto, Federica,Pace, Paola,Pescatore, Giovanna,Scarpelli, Rita,Stillmock, Kara,Witmer, Marc V.,Rowley, Michael
experimental part, p. 5843 - 5855 (2009/09/25)
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.
Dihydroxypyrimidine-4-carboxamides as novel potent and selective HIV integrase inhibitors
Pace, Paola,Di Francesco, M. Emilia,Gardelli, Cristina,Harper, Steven,Muraglia, Ester,Nizi, Emanuela,Orvieto, Federica,Petrocchi, Alessia,Poma, Marco,Rowley, Michael,Scarpelli, Rita,Laufer, Ralph,Paz, Odalys Gonzalez,Monteagudo, Edith,Bonelli, Fabio,Hazuda, Daria,Stillmock, Kara A.,Summa, Vincenzo
, p. 2225 - 2239 (2007/10/03)
Human immunodeficiency virus type-1 (HIV-1) integrase, one of the three constitutive viral enzymes required for replication, is a rational target for chemotherapeutic intervention in the treatment of AIDS that has also recently been confirmed in the clinical setting. We report here on the design and synthesis of N-benzyl-5,6-dihydroxypyrimidine-4-carboxamides as a class of agents which exhibits potent inhibition of the HIV-integrase-catalyzed strand transfer process. In the current study, structural modifications on these molecules were made in order to examine effects on HIV-integrase inhibitory potencies. One of the most interesting compounds for this series is 2-[1-(dimethylamino)-1-methylethyl]-N-(4-fluorobenzyl)-5,6-dihydroxypyrimidine- 4-carboxamide 38, with a CIC95 of 78 nM in the cell-based assay in the presence of serum proteins. The compound has favorable pharmacokinetic properties in preclinical species (rats, dogs, and monkeys) and shows no liabilities in several counterscreening assays, highlighting its potential as a clinically useful antiviral agent.
