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Shawn J Stachel,
Thomas G Steele, Alessia Petrocchi,
Sharie J Haugabook,
Georgia McGaughey,
M Katharine Holloway,
Timothy Allison,
Sanjeev Munshi,
Paul Zuck,
Dennis Colussi,
Katherine Tugasheva,
Abigail Wolfe,
Samuel L Graham,
Joseph P Vacca
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ABSTRACT: We have developed a novel series of pyrrolidine derived BACE-1 inhibitors. The potency of the weak initial lead structure was enhanced using library-based SAR methods. The series was then further advanced by rational design while maintaining a minimal ligand binding efficiency threshold. Ultimately, the co-crystal structure was obtained revealing that these inhibitors interacted with the enzyme in a unique fashion. In all, the potency of the series was enhanced by 4 orders of magnitude from the HTS lead with concomitant increases in physical properties needed for series advancement. The progression of these developments in a systematic fashion is described.
Bioorganic & medicinal chemistry letters 11/2011; 22(1):240-4. · 2.65 Impact Factor
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Steven Harper,
Marco Ferrara,
Benedetta Crescenzi,
Marco Pompei,
Maria Cecilia Palumbi,
Jillian M DiMuzio,
Monica Donghi,
Fabrizio Fiore,
Uwe Koch,
Nigel J Liverton,
Silvia Pesci, Alessia Petrocchi,
Michael Rowley,
Vincenzo Summa,
Cristina Gardelli
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ABSTRACT: In a follow-up to our recent disclosure of P2-P4 macrocyclic inhibitors of the hepatitis C virus (HCV) NS3 protease (e.g., 1, Chart 1), we report a new but related compound series featuring a basic amine at the N-terminus of the P3-amino acid residue. Replacement of the electroneutral P3-amino acid capping group (which is a feature of almost all tripeptide-like inhibitors of NS3 reported to date) with a basic group is not only tolerated but can result in advantageous cell based potency. Optimization of this new class of P3-amine based inhibitors gave compounds such as 25 and 26 that combine excellent cell based activity with pharmacokinetic properties that are attractive for an antiviral targeting HCV.
Journal of Medicinal Chemistry 08/2009; 52(15):4820-37. · 4.80 Impact Factor
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ABSTRACT: A novel class of tetrahydro-pyrazinopyrimidine-2-carboxamides have been identified as HIV-1 integrase inhibitors. Optimization of the initial lead culminated in the discovery of a series of compounds with high potency on the enzyme and an antiviral cell-based activity equivalent to that showed by Raltegravir, the first in class HIV-1 integrase inhibitor.
Bioorganic & medicinal chemistry letters 06/2009; 19(15):4245-9. · 2.65 Impact Factor
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Vincenzo Summa, Alessia Petrocchi,
Fabio Bonelli,
Benedetta Crescenzi,
Monica Donghi,
Marco Ferrara,
Fabrizio Fiore,
Cristina Gardelli,
Odalys Gonzalez Paz,
Daria J Hazuda, [......],
Edith Monteagudo,
Ester Muraglia,
Emanuela Nizi,
Federica Orvieto,
Paola Pace,
Giovanna Pescatore,
Rita Scarpelli,
Kara Stillmock,
Marc V Witmer,
Michael Rowley
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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.
Journal of Medicinal Chemistry 10/2008; 51(18):5843-55. · 4.80 Impact Factor
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Paola Pace,
M Emilia Di Francesco,
Cristina Gardelli,
Steven Harper,
Ester Muraglia,
Emanuela Nizi,
Federica Orvieto, Alessia Petrocchi,
Marco Poma,
Michael Rowley,
Rita Scarpelli,
Ralph Laufer,
Odalys Gonzalez Paz,
Edith Monteagudo,
Fabio Bonelli,
Daria Hazuda,
Kara A Stillmock,
Vincenzo Summa
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ABSTRACT: 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.
Journal of Medicinal Chemistry 05/2007; 50(9):2225-39. · 5.25 Impact Factor
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ABSTRACT: 4,5-Dihyroxypyrimidine carboxamides, which evolved from a related series of HCV NS5b polymerase inhibitors, have been optimized to provide selective HIV integrase strand transfer inhibitors. Extensive SAR around the benzylamide moiety led to the identification of the p-fluorobenzylamide as optimal in the enzymatic assay.
Bioorganic & Medicinal Chemistry Letters 02/2007; 17(2):350-3. · 2.55 Impact Factor
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Philip Jones,
Sergio Altamura,
Prasun K Chakravarty,
Ottavia Cecchetti,
Raffaele De Francesco,
Paola Gallinari,
Raffaele Ingenito,
Peter T Meinke, Alessia Petrocchi,
Michael Rowley,
Rita Scarpelli,
Sergio Serafini,
Christian Steinkühler
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ABSTRACT: Histone deacetylase (HDAC) inhibitors offer a promising strategy for cancer therapy and the first generation HDAC inhibitors are currently in clinical trials. A structurally novel series of HDAC inhibitors based on the natural cyclic tetrapeptide Apicidin is described. Selected screening of the sample collection looking for L-2-amino-8-oxodecanoic acid (L-Aoda) derivatives identified a small acyclic lead molecule 1 with the unusual ketone zinc binding group. SAR studies around this lead resulted in optimization to potent, low molecular weight, selective, non-hydroxamic acid HDAC inhibitors, equipotent to current clinical candidates.
Bioorganic & Medicinal Chemistry Letters 01/2007; 16(23):5948-52. · 2.55 Impact Factor
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ABSTRACT: The dihydroxypyrimidine carboxamide 4a was discovered as a potent and selective HIV integrase strand transfer inhibitor. The optimization of physicochemical properties, pharmacokinetic profiles, and potency led to the identification of 13 in the dihydroxypyrimidine series and 18 in the N-methylpyrimidinone series having low nanomolar activity in the cellular HIV spread assay in the presence of 50% normal human serum and very good pharmacokinetics in preclinical species.
Journal of Medicinal Chemistry 12/2006; 49(23):6646-9. · 5.25 Impact Factor
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ABSTRACT: A new class of the HCV NS5b RNA-dependent RNA polymerase inhibitors, the dihyroxypyrimidinecarboxylic acid derivative, was designed from a diketoacid and meconic acid derivative discovered by screening. Mechanism of action and essential moieties required for activity were identified. The corresponding N-methylpyrimidinone was also prepared; both classes are novel, reversible, and selective inhibitors of the HCV NS5b polymerase with improved druglike characteristics.
Journal of Medicinal Chemistry 11/2004; 47(22):5336-9. · 5.25 Impact Factor
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ABSTRACT: alpha,gamma-Diketo acids (DKA) were discovered from screening as selective and reversible inhibitors of hepatitis C virus NS5b RNA-dependent RNA polymerase. The diketo acid moiety proved essential for activity, while substitution on the gamma position was necessary for selectivity and potency. Optimization led to the identification of a DKA inhibitor of NS5b polymerase with IC(50) = 45 nM, one of the most potent HCV NS5b polymerase inhibitors reported.
Journal of Medicinal Chemistry 02/2004; 47(1):14-7. · 5.25 Impact Factor
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ABSTRACT: α,γ-Diketo acids (DKA) were discovered from screening as selective and reversible inhibitors of hepatitis C virus NS5b RNA-dependent RNA polymerase. The diketo acid moiety proved essential for activity, while substitution on the γ position was necessary for selectivity and potency. Optimization led to the identification of a DKA inhibitor of NS5b polymerase with IC50 = 45 nM, one of the most potent HCV NS5b polymerase inhibitors reported.
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