Discovery of 4-((1-(1H-imidazol-2-yl)alkoxy)methyl)pyridines as a new class of Trypanosoma cruzi growth inhibitors.

The identification of a new series of growth inhibitors of Trypanosoma cruzi, the causative agent of Chagas' disease, is described. In vitro screening of a subset of compounds from our in-house compound collection against the parasite led to the identification of hit compound 1 with low micromolar inhibition of T. cruzi growth. SAR exploration on the hit compound led to the identification of compounds that show nanomolar parasite growth inhibition (T. cruzi EC50 ≤ 100 nM) and no cytotoxicity in human cells (HeLa CC50 > 50 µM). Further investigation identified CYP51 inhibition (compound 11 CYP51 IC50 52 nM) as a possible mechanism of action of this new class of anti-parasitic agents.

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.

Improved Selective Class I HDAC and Novel Selective HDAC3 Inhibitors: Beyond Hydroxamic Acids and Benzamides.

The application of class I HDAC inhibitors as cancer therapies is well established, but more recently their development for nononcological indications has increased. We report here on the generation of improved class I selective human HDAC inhibitors based on an ethylketone zinc binding group (ZBG) in place of the hydroxamic acid that features the majority of HDAC inhibitors. We also describe a novel set of HDAC3 isoform selective inhibitors that show stronger potency and selectivity than the most commonly used HDAC3 selective tool compound RGFP966. These compounds are again based on an alternative ZBG with respect to the ortho-anilide that is featured in HDAC3 selective compounds reported to date.

Integrase inhibitors for the treatment of HIV infection.

HIV-1 integrase catalyzes the insertion of HIV-1 DNA into the genome of the host cell and, therefore, represents a rational target for chemotherapeutic intervention in the treatment of HIV-1 infection. Raltegravir, marketed as Isentress, is the first integrase inhibitor to be approved by the FDA for the treatment of HIV AIDS infection. This review briefly describes the successful medicinal chemistry efforts that culminated in the discovery of raltegravir, and highlights more recent progress that has been made in the field of HIV-1 integrase inhibition.

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.

Development of 2-t butyl-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.

Dihydroxypyrimidine-4-carboxamides as novel potent and selective HIV integrase inhibitors.

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.

Discovery and synthesis of HIV integrase inhibitors: development of potent and orally bioavailable N-methyl pyrimidones.

The human immunodeficiency virus type-1 (HIV-1) encodes three enzymes essential for viral replication: a reverse transcriptase, a protease, and an integrase. The latter is responsible for the integration of the viral genome into the human genome and, therefore, represents an attractive target for chemotherapeutic intervention against AIDS. A drug based on this mechanism has not yet been approved. Benzyl-dihydroxypyrimidine-carboxamides were discovered in our laboratories as a novel and metabolically stable class of agents that exhibits potent inhibition of the HIV integrase strand transfer step. Further efforts led to very potent compounds based on the structurally related N-Me pyrimidone scaffold. One of the more interesting compounds in this series is the 2-N-Me-morpholino derivative 27a, which shows a CIC95 of 65 nM in the cell in the presence of serum. The compound has favorable pharmacokinetic properties in three preclinical species and shows no liabilities in several counterscreening assays.

4,5-dihydroxypyrimidine carboxamides and N-alkyl-5-hydroxypyrimidinone carboxamides are potent, selective HIV integrase inhibitors with good pharmacokinetic profiles in preclinical species.

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.

HCV NS5b RNA-dependent RNA polymerase inhibitors: from alpha,gamma-diketoacids to 4,5-dihydroxypyrimidine- or 3-methyl-5-hydroxypyrimidinonecarboxylic acids. Design and synthesis.

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.

Discovery of alpha,gamma-diketo acids as potent selective and reversible inhibitors of hepatitis C virus NS5b RNA-dependent RNA polymerase.

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.

Synthesis of Medium-Ring Nitrogen Heterocycles via Palladium-Catalyzed Heteroannulation of 1,2-Dienes.

Seven-, eight-, and nine-membered-ring nitrogen heterocycles are readily prepared by the palladium-catalyzed heteroannulation of a variety of 1,2-dienes by a range of tosylamide- and amine-containing aryl and vinylic halides. The ease of ring formation is seven > eight > nine, and better results are obtained using aryl halides, rather than vinylic halides, and tosylamide functionality, rather than amine functionality. The reaction is suggested to proceed by the formation and addition of an aryl or vinylic palladium compound to the allene to generate a pi-allylpalladium intermediate, which subsequently undergoes nucleophilic displacement of palladium at the less hindered end of the pi-allyl system.

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.

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.

The monoethyl ester of meconic acid is an active site inhibitor of HCV NS5B RNA-dependent RNA polymerase.

Screening of the in-house sample collection for compounds with HCV NS5B RNA dependent RNA polymerase inhibition led to the identification of a new lead. Afterwards, we discovered that the screening lead, rather than containing the expected structure 1, was comprised of roughly a 1:1 mixture of meconic acid 2 and its monoethyl ester 3, with all inhibitory potency residing with 3. We propose that this compound shares critical common features for activity with alpha,gamma-diketoacids inhibitors previously discovered by our group. SAR around this molecule will be presented to provide an improved basis for structure-based ligand design.

Incidencia del bienestar psicológico en el uso de estrategias de afrontamiento: un estudio con adolescentes de Tucumán (Argentina) / The incidence of psychological well being of coping strategies: Tucumán's adolescents study

Se informa sobre las estrategias de afrontamiento utilizadas por adolescentes escolarizados de 15 a 18 años de nivel socioeconómico alto de Tucumán (Argentina). Las estrategias de afrontamiento fueron analizadas en relación al nivel de Bienestar Psicológico. La muestra, de carácter intencional, no aleatoria, estuvo constituida por 150 adolescentes (varones y mujeres) de Tucumán.Se administró la Escala BIEPS (Bienestar Psicológico), adaptación Casullo y la Escala de Afrontamiento para Adolescentes, adaptación española (ACS, forma general). Inicialmente, se analizó el nivel de Bienestar Psicológico de los adolescentes y las estrategias de afrontamiento más utilizadas. Posteriormente, se realizó la correlación entre nivel de Bienestar y estrategias de afrontamiento. Se concluye que las estrategias de afrontamiento más utilizadas son Preocuparse, Buscar diversiones relajantes, Buscar pertenencia, Distracción física y Concentrarse en resolver el problema. Además, los jóvenes con alto Bienestar utilizan estrategias que resuelven el conflicto, mientras que los que obtuvieron bajo bienestar presentan estrategias improductivas.

Bienestar psicológico y estrategias de afrontamiento en adolescentes escolarizados de Tucumán (13 y 14 años) / Psychological well-being and coping strategies in scholar adolescents of Tucumán (13 and 14 years old)

Se comunican resultados obtenidos a partir de una investigación sobre bienestar psicológico y estrategias de afrontamiento con estudiantes adolescentes de 13 y 14 años de S. M. de Tucumán. Se administraron las Escalas de Bienestar Psicológico (BIEPS) y Afrontamiento (ACS), ambas adaptación Casullo. Se trata de un estudio descriptivo-comparativo realizado en una muestra de 247 varones y mujeres. Se analizó la distribución de la muestra según el criterio de alto y bajo bienestar, se correlacionaron estos datos con las 18 estrategias de afrontamiento. Se evaluó la “Situación Problemática” (ACS-1ª Parte) y la “Preocupación Principal” (ACS-2ª Parte) y se realizó un análisis comparativo según género. Se fundamenta la importancia atribuida al tema por la íntima vinculación del concepto “bienestar psicológico” con el de salud integral y como un componente indispensable del desarrollo humano. La investigación realizada aporta datos empíricos para el diseño de programas de prevención con adolescentes no consultantes.