Paola Pace

Discovery of Raltegravir, a Potent, Selective Orally Bioavailable HIV-Integrase Inhibitor for the Treatment of HIV-AIDS Infection

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.

4-Hydroxy-5-pyrrolinone-3-carboxamide HIV-1 integrase inhibitors.

The viral enzyme integrase is essential for the replication of HIV-1 and, after the discovery of Isentress, represents a validated target for anti-retroviral therapy. Incorporation of the dihydroxycarbonyl pharmacophore into a pyrrolinone scaffold led to the discovery of 5-pyrrolinone-3-carboxamides as a structurally diverse class of HIV-1 integrase inhibitors.

Synthesis of nitrogen heterocycles via Pd-catalyzed cross-coupling of o-alkenyl anilides with vinylic halides and triflates

Abstract The palladium-catalyzed cross-coupling of o -allylic and o -vinylic anilides with vinylic halides and triflates produces substituted nitrogen heterocycles in good to high yields by a process involving vinylpalladium addition to the olefin, rearrangement to a π-allylpalladium intermediate and subsequent intramolecular nucleophilic displacement of palladium. Different reactivity and regioselectivity in the palladium migration have been observed with different substituted alkenyl anilides.

Synthesis of 2-vinylic dihydroindoles and tetrahydroquinolines via Pd-catalyzed cross-coupling of o-alkenyl anilides with vinylic halides and triflates

The palladium-catalyzed cross-coupling of o-vinylic and o-allylic anilides with vinylic halides and triflates produces 2-vinylic dihydroindoles and tetrahydroquinolines respectively in good to high yields.

Synthesis of unexpected nitrogen heterocycles via Pd-catalyzed cross-coupling of o-isopropenyl and methallyl anilides with vinylic halides

Abstract The palladium-catalyzed cross-coupling of o -isopropenyl and o -methallyl- N -tosylanilides with vinylic halides affords good yields of unexpected substituted dihydroquinolines and dihydroindoles respectively, apparently via vinylpalladium addition to the olefin and an unusual rearrangement to a π-allylpalladium intermediate.

Development of 2-tbutyl-N-methyl pyrimidones as potent inhibitors of HIV integrase

A series of novel 2-(t)butyl-N-methyl pyrimidone HIV-1 integrase inhibitors have been identified. Optimization of the initial lead resulted in compounds such as 9d and 14a, which showed high levels of activity in cell culture inhibiting viral replication with CIC(95) of 10nM in the presence of 50% normal human serum.

Palladium-catalyzed cross-coupling of unsaturated phenols with vinylic halides and triflates

Abstract The palladium-catalyzed cross-coupling of o -vinylic phenols with vinylic halides and triflates produces substituted dihydrobenzopyrans and dihydrobenzofurans respectively in good to high yields.

Novel P2-P4 macrocyclic inhibitors of HCV NS3/4A protease by P3 succinamide fragment depeptidization strategy.

Hepatitis C represents a serious worldwide health-care problem. Recently, we have disclosed a novel class of P2-P4 macrocyclic inhibitors of NS3/4A protease containing a carbamate functionality as capping group at the P3 N-terminus. Herein we report our work aimed at further depeptidizing the P3 region by replacement of the urethane function with a succinamide motif. This peptidomimetic approach has led to the discovery of novel P2-P4 macrocyclic inhibitors of HCV NS3/4A protease with sub-nanomolar enzyme affinities. In addition to being potent inhibitors of HCV subgenomic replication, optimized analogues within this series have also presented attractive PK properties and showed promising liver levels in rat following oral administration.

Synthesis of oxygen heterocycles via Pd-catalyzed cross-coupling of unsaturated phenols and vinylic halides or triflates

Abstract The palladium-catalyzed cross-coupling of o-allylic and o-vinylic phenols with vinylic halides and triflates produces substituted dihydrobenzopyrans and dihydrobenzofurans respectively in good to high yields. The proposed mechanism involves vinylpalladium addition to the olefin, rearrangement to a π-allylpalladium intermediate and subsequent intramolecular nucleophilic displacement of palladium.

Novel Macrocyclic Inhibitors of Hepatitis C NS3/4A Protease Featuring a 2-Amino-1,3-thiazole as a P4 Carbamate Replacement

Our laboratories recently reported the discovery of P2-P4 macrocyclic inhibitors of HCV NS3/4A protease, characterized by high levels of potency and liver exposure. Within this novel class of inhibitors, we here describe the identification of a structurally diverse series of compounds featuring a 2-amino-1,3-thiazole as replacement of the carbamate in P4. Optimization studies focused on structural modifications in the P3, P2, and P1 regions of the macrocycle as well as on the linker chain and resulted in the discovery of several analogues characterized by excellent levels of enzyme and cellular activity. Among these, compound 59 displayed an attractive pharmacokinetic profile in preclinical species and showed sustained liver levels following oral administration in rats.