4-Aryl-3-arylsulfonyl-quinolines as negative allosteric modulators of metabotropic GluR5 receptors:From HTS hit to development candidate

High throughput screening of our corporate compound library followed by hit-to-lead development resulted in a 4-aryl-3-arylsulfonyl-quinoline derivative lead (2) with mGluR5 negative allosteric modulator activity. During the lead optimization process, our objective was to improve affinity and metabolic stability. Modifications at the three targeted regions of the lead structure resulted in compounds with nanomolar affinity and acceptable metabolic stability. One of the most promising compounds (3), showing excellent in vivo efficacy, was selected for preclinical development and subsequent phase I clinical studies

Sustainable performance evaluation of urban mobility projects using multicriteria group decision making approach

Grandhi, S ORCiD: 0000-0001-9704-7822; Wibowo, S ORCiD: 0000-0002-5318-8428This paper presents a multicriteria group decision making approach for effectively evaluating the sustainable performance of urban mobility projects. The subjectiveness and imprecision of the performance evaluation process is adequately modeled by using intuitionistic fuzzy numbers. To avoid the complex and unreliable process of comparing fuzzy numbers usually required in fuzzy multicriteria decision making, an efficient algorithm is developed based on the degree of indeterminacy and the degree of similarities. An example is presented to demonstrate the applicability of the approach

Breakthroughs in Medicinal Chemistry: New targets and mechanisms, new drugs, new hopes

The Editorial Board of the Medicinal Chemistry section of the journal Molecules publishes here its first Editorial, which has been prepared by highlighting, in sub-editorials of about one hundred words, some selected recently published articles that may have a profound impact on drug discovery and therapy. In particular, this editorial highlights new drug targets and mechanisms of action and new classes of drugs, as well as new therapeutic uses for known drugs or the involvement of known biological targets in new diseases. We also discuss some structural biology studies and new computational tools that may pave the way for the rational design or identification of more efficacious and safer drugs. Overall, the findings reported in these highlighted papers raise our hopes for the management of difficult-to-treat diseases that are posing a growing health threat, with new or repurposed drugs that overcome the limitations of currently applied therapies