Discovery and Optimization of Orally Bioavailable Phthalazone and Cinnolone Carboxylic Acid Derivatives as S1P2 Antagonists against Fibrotic Diseases.

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive lung disease. Current treatments only slow down disease progression, making new therapeutic strategies compelling. Increasing evidence suggests that S1P2 antagonists could be effective agents against fibrotic diseases. Our compound collection was mined for molecules possessing substructure features associated with S1P2 activity. The weakly potent indole hit 6 evolved into a potent phthalazone series, bearing a carboxylic acid, with the aid of a homology model. Suboptimal pharmacokinetics of a benzimidazole subseries were improved by modifications targeting potential interactions with transporters, based on concepts deriving from the extended clearance classification system (ECCS). Scaffold hopping, as a part of a chemical enablement strategy, permitted the rapid exploration of the position adjacent to the carboxylic acid. Compound 38, with good pharmacokinetics and in vitro potency, was efficacious at 10 mg/kg BID in three different in vivo mouse models of fibrotic diseases in a therapeutic setting.

Didactic platform for DC motor speed and position control in Z-plane.

This paper describes how to implement a low-cost didactic platform designed to teach or reinforce discrete control theory concepts. The controllers used in this work (P, PI, PD, and PID) are suitable for undergraduate students but the same platform could be used to explain and test advanced controllers to graduate students. This document shows, step by step, how to control a DC motor speed and position, along with the most common problems and its solutions, commonly overlooked in the literature. It also explains how to simulate the system behavior and compares the simulations with the real data, showing an average correlation coefficient of ρ=0.983.

Triazolopyridines as selective JAK1 inhibitors: from hit identification to GLPG0634.

Janus kinases (JAK1, JAK2, JAK3, and TYK2) are involved in the signaling of multiple cytokines important in cellular function. Blockade of the JAK-STAT pathway with a small molecule has been shown to provide therapeutic immunomodulation. Having identified JAK1 as a possible new target for arthritis at Galapagos, the compound library was screened against JAK1, resulting in the identification of a triazolopyridine-based series of inhibitors represented by 3. Optimization within this chemical series led to identification of GLPG0634 (65, filgotinib), a selective JAK1 inhibitor currently in phase 2B development for RA and phase 2A development for Crohn's disease (CD).

Type II kinase inhibitors: an opportunity in cancer for rational design.

With the advent of the Type II kinase inhibitor imatinib (Gleevec) for treatment against cancer, rational design of tailored molecules has brought a revolution in medicinal chemistry for treating tumours caused by kinase malfunctioning. Among different types of kinase inhibitors, the design of Type II inhibitors has been rationalized for maximizing the benefits and reducing drawbacks. Here we highlight the development made in Type II inhibitors, discussing the advantages and disadvantages of these types of molecules. Furthermore, we present the strategies for designing druggable molecules that either selectively inhibit target kinases or overcome drug resistance.

Exploring neoglycoprotein assembly through native chemical ligation using neoglycopeptide thioesters prepared via N-->S acyl transfer.

Sugars and simplified oligosaccharide "mimics" can be joined with protein fragments at pre-defined sites using reliable chemical reactions such as thiol alkylation and Cu(I) catalysed azide/acetylene ligation (click chemistry). These fragments have the potential to be assembled into neoglycoprotein therapeutics using native chemical ligation.

A novel neoglycopeptide linkage compatible with native chemical ligation.

The straightforward synthesis of a novel class of neoglycopeptide and its fusion with a larger peptide thioester using sequential chemoselective ligations is described.

Enantiomer separation by countercurrent chromatography using cinchona alkaloid derivatives as chiral selectors.

Cinchona-derived anion-exchange-type chiral selectors have been adapted and employed in countercurrent chromatography (CCC) for the separation of enantiomers of N-derivatized amino acids and 2-aryloxypropionic acids. The accurate optimization of the enantioseparation in terms of solvent system composition, pH values, ionic strength, and CCC operating conditions was performed. A wide range of solvent mixtures was evaluated. Successful resolutions were achieved in systems such as ammonium acetate buffer/tert-amyl alcohol/methanol/heptane and especially ammonium acetate buffer/methyl isobutyl ketone or diisopropyl ether. Up to 300 mg (0.92 mmol) of N-(3,5-dinitrobenzoyl)-(+/-)-leucine was totally resolved in a single run using a 10 mM concentration of chiral selector in 122 mL of stationary phase. This amount could be increased up to 900 mg (2.77 mmol) when pH-zone-refining mode was applied. The results here presented account for the high potential of CCC as a preparative enantiomer separation technique.