title: Discovery of raltegravir, a potent, selective orally bioavailable HIV-integrase inhibitor for the treatment of HIV-AIDS infection.
abstract: 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.
authors.affiliation: Istituto Di Ricerche Di Biologia Molecolare, P. Angeletti SpA (Merck Research Laboratories, Rome), Via Pontina Km 30, 600,00040 Pomezia, Italy. vincenzo_summa@merck.com
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Summa
authors.forename: Alessia
authors.initials: A
authors.lastname: Petrocchi
authors.forename: Fabio
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authors.lastname: Bonelli
authors.forename: Benedetta
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authors.lastname: Crescenzi
authors.forename: Monica
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authors.lastname: Donghi
authors.forename: Marco
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authors.lastname: Ferrara
authors.forename: Fabrizio
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authors.lastname: Fiore
authors.forename: Cristina
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authors.lastname: Gardelli
authors.forename: Odalys
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authors.lastname: Gonzalez Paz
authors.forename: Daria J
authors.initials: DJ
authors.lastname: Hazuda
authors.forename: Philip
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authors.lastname: Jones
authors.forename: Olaf
authors.initials: O
authors.lastname: Kinzel
authors.forename: Ralph
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authors.lastname: Laufer
authors.forename: Edith
authors.initials: E
authors.lastname: Monteagudo
authors.forename: Ester
authors.initials: E
authors.lastname: Muraglia
authors.forename: Emanuela
authors.initials: E
authors.lastname: Nizi
authors.forename: Federica
authors.initials: F
authors.lastname: Orvieto
authors.forename: Paola
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authors.lastname: Pace
authors.forename: Giovanna
authors.initials: G
authors.lastname: Pescatore
authors.forename: Rita
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authors.lastname: Scarpelli
authors.forename: Kara
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authors.lastname: Stillmock
authors.forename: Marc V
authors.initials: MV
authors.lastname: Witmer
authors.forename: Michael
authors.initials: M
authors.lastname: Rowley