-(2-Aminophenyl)-benzamide Inhibitors of Class I HDAC Enzymes with Antiproliferative and Antifibrotic Activity.

Inhibitors of histone deacetylases (HDACs) have received special attention as novel anticancer agents. Among various types of synthetic inhibitors, benzamides constitute an important class, and one is an approved drug (chidamide). Here, we present a novel class of HDAC inhibitors containing the -(2-aminophenyl)-benzamide functionality as the zinc-binding group linked to various cap groups, including the amino acids pyroglutamic acid and proline.

Synthesis of novel 2-pyrrolidinone and pyrrolidine derivatives and study of their inhibitory activity against autotaxin enzyme.

Autotaxin (ATX), a glycoprotein (~125 kDa) isolated as an autocrine motility factor from melanoma cells, belongs to a seven-membered family of ectonucleotide pyrophosphatase/phosphodiesterase (ENPP), and exhibits lysophospholipase D activity. ATX is responsible for the hydrolysis of lysophosphatidylcholine (LPC) to produce the bioactive lipid lysophosphatidic acid (LPA), which is upregulated in a variety of pathological inflammatory conditions, including fibrosis, cancer, liver toxicity and thrombosis. Given its role in human disease, the ATX-LPA axis is an interesting target for therapy, and the development of novel potent ATX inhibitors is of great importance.

Rational drug design paradigms: the odyssey for designing better drugs.

Due to the time and effort requirements for the development of a new drug, and the high attrition rates associated with this developmental process, there is an intense effort by academic and industrial researchers to find novel ways for more effective drug development schemes. The first step in the discovery process of a new drug is the identification of the lead compound. The modern research tendency is to avoid the synthesis of new molecules based on chemical intuition, which is time and cost consuming, and instead to apply in silico rational drug design.

Autotaxin inhibitors: a patent review.

Introduction: Autotaxin (ATX) is a lysophospholipase D enzyme that hydrolyzes lysophosphatidylcholine to lysophosphatidic acid (LPA) and choline. LPA is a bioactive lipid mediator that activates several transduction pathways, and is involved in migration, proliferation and survival of various cells. Thus, ATX is an attractive medicinal target.

Synthesis of new optically active 2-pyrrolidinones.

A new class of optically active 2-pyrrolidinones was synthesized, starting from S-pyroglutamic acid, a well known natural chiral synthon. The synthetic design followed led to the insertion of various substituents at positions 1 and 5 of the 2-pyrrolidinone ring, including the imidazole moiety. Some of them possess two or three stereogenic centers, the configuration of which was retained under the mild conditions used.

Synthesis, in silico docking experiments of new 2-pyrrolidinone derivatives and study of their anti-inflammatory activity.

A new class of 2-pyrrolidinone derivatives was designed, synthesized, and tested for their antioxidant and anti-inflammatory activities. The compounds were evaluated for their inhibitory activity against LOX. The most potent among them, 14d [IC(50) 0.

Development of accurate binding affinity predictions of novel renin inhibitors through molecular docking studies.

In this study, an attempt was made to explore a possible correlation between different docking scoring functions (Glide InducedFit docking score and GOLD's GoldScore and ChemScore) and binding energy values of a set of renin inhibitors, using linear regression model. The renin inhibitors under study are characterized by known bound to the receptor crystal structures possessing a great variety of pharmacophore groups and a wide range of IC₅₀ values. Linear regression models were derived to relate the docking scoring function and pIC₅₀ values of renin inhibitors under study.

Hypertension study in anaesthetized rabbits: protocol proposal for AT1 antagonists screening.

Introduction: The aim of this study was to establish an optimized fast and safe protocol for the pharmacological screening of AT(1) antagonists.

Materials And Methods: The pharmaceutical prototype AT(1) antagonist losartan, its active metabolite EXP3174 and the synthetic compound MMK1 were analysed in order to validate the protocol. Ang II was continuously infused while the animals received the drugs in two procedures.

Application of 3D QSAR CoMFA/CoMSIA and in silico docking studies on novel renin inhibitors against cardiovascular diseases.

For the first time, a set of renin inhibitors were subjected to the 3D QSAR/CoMFA and CoMSIA studies. The utility of renin inhibitors in the treatment of cardiovascular diseases has not been fully explored yet. At the moment, aliskiren is the first and only existing renin inhibitor in the drug market.

Structure-activity relationship of 2-oxoamide inhibition of group IVA cytosolic phospholipase A2 and group V secreted phospholipase A2.

The Group IVA cytosolic phospholipase A2 (GIVA cPLA2) is a key provider of substrates for the production of eicosanoids and platelet-activating factor. We explored the structure-activity relationship of 2-oxoamide-based compounds and GIVA cPLA2 inhibition. The most potent inhibitors are derived from delta- and gamma-amino acid-based 2-oxoamides.

Synthesis of lipophilic 2-oxoamides based on gamma-aminobutyric and delta-aminovaleric analogues and their activity against phospholipase A2.

A variety of lipophilic 2-oxoamides based on gamma-aminobutyric and delta-aminovaleric analogues were synthesized. 2-oxoamides containing a tetrazole, a thioethyl or a thioacetyl group are weak inhibitors of GIVA cPLA(2), while derivatives containing a methyl tetrazole, a diethyl phosphonate or a thioethyl group are weak inhibitors of GV sPLA(2).

Synthesis of tetrazole analogs of gamma- and delta-amino acids.

N-benzyloxycarbonyl-protected alpha- or beta-amino alcohols, easily prepared from alpha- and beta-amino acids, were converted into aldehydes and directly reacted with (triphenyl phosphoranylidene) acetonitrile, leading to unsaturated nitriles. Treatment of nitriles with NaN(3) and ZnBr(2) produced unsaturated gamma- and delta-amino tetrazoles, which were deprotected and converted to the corresponding saturated compounds by catalytic hydrogenation. For the case of delta-amino tetrazole, the methylation of the acidic moiety occurred after treatment with CH(2)N(2), leading to the N(1)- and N(2)-methylated constitutional isomers, which were separated by column chromatography and hydrogenated.