BACKGROUND AND PURPOSEPulmonary arterial hypertension (PAH) is characterized by enhanced pulmonary vascular resistance, right ventricular hypertrophy and increased right ventricular systolic pressure. Here, we investigated the effects of a N-acylhydrazone derivative, 3,4-dimethoxyphenyl-N-methyl-benzoylhydrazide (LASSBio-1359), on monocrotaline (MCT)-induced pulmonary hypertension in rats.
EXPERIMENTAL APPROACHPAH was induced in male Wistar rats by a single i.p. injection of MCT (60 mg·kg −1 ) and 2 weeks later, oral LASSBio-1359 (50 mg·kg −1 ) or vehicle was given once daily for 14 days. Echocardiography was used to measure cardiac function and pulmonary artery dimensions, with histological assay of vascular collagen. Studies of binding to human recombinant adenosine receptors (A1, A2A, A3) and of docking with A2A receptors were also performed.
KEY RESULTSMCT administration induced changes in vascular and ventricular structure and function, characteristic of PAH. These changes were reversed by treatment with LASSBio-1359. MCT also induced endothelial dysfunction in pulmonary artery, as measured by diminished relaxation of pre-contracted arterial rings, and this dysfunction was reversed by LASSBio-1359. In pulmonary artery rings from normal Wistar rats, LASSBio-1359 induced relaxation, which was decreased by the adenosine A2A receptor antagonist, ZM 241385. In adenosine receptor binding studies, LASSBio-1359 showed most affinity for the A2A receptor and in the docking analyses, binding modes of LASSBio-1359 and the A2A receptor agonist, CGS21680, were very similar.
CONCLUSION AND IMPLICATIONSIn rats with MCT-induced PAH, structural and functional changes in heart and pulmonary artery were reversed by treatment with oral LASSBio-1359, most probably through the activation of adenosine A2A receptors.
In the last century, only six patents disclosing NAH derivatives for therapeutic purposes were published, and only in 2010, this subunit started receiving some real attention regarding its therapeutic potential. In this review, the Brazilian and Chinese Universities were identified as the major patent applicants, especially for drug candidates for the treatment of chronic pain, inflammatory disorders and cancer. The NAH subunit is very versatile both from synthetic and medicinal chemistry point of view. This feature is a direct result from the conformational diversity that this framework presents, achievable by subtle and simple chemical changes. Therefore, our opinion is that this moiety suits a lot more drug discovery projects than it seems to at first glance. In conclusion, we strongly support and encourage a raise in the use of this unique subunit.
A SARS-CoV-2 main protease (MPRO) inhibitor was discovered employing molecular docking and a fragment-based pharmacophore model as virtual screening strategies.
During the early preclinical phase, from hit identification and optimization to a lead compound,
several medicinal chemistry strategies can be used to improve potency and/or selectivity. The
conformational restriction is one of these approaches. It consists of introducing some specific structural
constraints in a lead candidate to reduce the overall number of possible conformations in order to favor
the adoption of a bioactive conformation and, as a consequence, molecular recognition by the target receptor.
In this work, we focused on the application of the conformational restriction strategy in the last
five years for the optimization of hits and/or leads of several important classes of therapeutic targets in
the drug discovery field. Thus, we recognize the importance of several kinase inhibitors to the current
landscape of drug development for cancer therapy and the use of G-protein Coupled Receptor (GPCR)
modulators. Several other targets are also highlighted, such as the class of epigenetic drugs. Therefore,
the possibility of exploiting conformational restriction as a tool to increase the potency and selectivity
and promote changes in the intrinsic activity of some ligands intended to act on many different targets
makes this strategy of structural modification valuable for the discovery of novel drug candidates.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.