Crystal structures of human and mouse ketohexokinase provide a structural basis for species- and isoform-selective inhibitor design.

A molecular understanding of the proteins involved in fructose metabolism is essential for controlling the current spread of fructose-related obesity, diabetes and related adverse metabolic states in Western populations. Fructose catabolism starts with the phosphorylation of D-fructose to fructose 1-phosphate by ketohexokinase (KHK). KHK exists in two alternatively spliced isoforms: the hepatic and intestinal isoform KHK-C and the peripheral isoform KHK-A. Here, the structure of apo murine KHK (mKHK), which differs from structures of human KHK in overall conformation, is reported. An isoform-selective ligand, which offers a 50-fold higher potency on mKHK and human KHK-A compared with KHK-C, is further characterized. In mKHK, large-scale conformational changes are observed upon ligand binding. The structures suggest a combined strategy for the design of species- and isoform-selective KHK inhibitors.

Identification of Highly Selective Orexin 1 Receptor Antagonists Driven by Structure-Based Design.

OX1 receptor antagonists are of interest to treat, for example, substance abuse disorders, personality disorders, eating disorders, or anxiety-related disorders. However, known dual OX1/OX2 receptor antagonists are not suitable due to their sleep-inducing effects; therefore, we were interested in identifying a highly OX1 selective antagonist with a sufficient window to OX2-mediated effects. Herein, we describe the design of highly selective OX1 receptor antagonists driven by the X-ray structure of OX1 with suvorexant, a dual OX1/OX2 receptor antagonist. Moderately selective OX1 antagonists comprising a [2.2.1]-bicyclic scaffold served as our starting point. Based on our binding mode hypothesis, we postulated which part of the scaffold points toward one of the regions where the two binding pockets differ. Structural changes in this part resulted in a modified core with higher inherent selectivity compared to the [2.2.1]-bicyclic template. The structure-based design, synthesis, and hit-to-lead evaluation of this novel OX1 receptor-selective scaffold are discussed herein.

Discovery of tetrahydroindazoles as a novel class of potent and in vivo efficacious gamma secretase modulators.

The identification and optimization of a novel series of centrally efficacious gamma secretase modulators (GSMs) offering an alternative to the privileged aryl imidazole motif is described. Chiral bicyclic tetrahydroindazolyl amine substituted triazolopyridines were identified as structurally distinct novel series of GSMs. Representative compound BI-1408 ((R)-42) was demonstrated to be centrally efficacious in rats at a 30 mg/kg oral dose.

Radical Difluoromethylation of Thiols with (Difluoromethyl)triphenylphosphonium Bromide.

A method for facile difluoromethylation of various thiols using (difluoromethyl)triphenylphosphonium bromide under mild reaction conditions is presented. The transformation proceeds in the absence of any transition metal using a bench-stable and readily accessible phosphonium salt. Deuterium labeling experiments and cyclic voltammetry measurements reveal that the difluoromethylation occurs via a SRN1-type mechanism. Substrate scope is broad, and various functional groups are tolerated (OH, NH2, amide, ester).

Poly(paraphenylene sulfide) and Poly(metaphenylene sulfide) via Light-Initiated SRN 1-Type Polymerization of Halogenated Thiophenols.

In this work, the synthesis of various halogenated thiophenol derivatives is presented. These thiophenols are used as monomers in light-initiated SRN 1-type radical polymerization reactions. The method provides easy access to industrially relevant poly(paraphenylene sulfide) and poly(metaphenylene sulfide). The influence of the halide leaving group and of other substituents in the thiophenol monomer on the polymerization process is investigated.

Synthesis of Chiral Piperazinones Using Amphoteric Aziridine Aldehyde Dimers and Functionalized Isocyanides.

We have evaluated a range of functionalized isocyanides in the aziridine aldehyde-driven multicomponent synthesis of piperazinones. High diasteroselectivity for each isocyanide was observed. A theoretical evaluation of the reaction course corroborates the experimental data. Moreover, the reactivity of cis- and trans-configured aziridine aldehyde dimers has been compared. This study further probes the dimer-driven mechanism of cyclization and enables an efficient access to a wide range of chiral piperazinones bearing functionalized side chains.

Light-induced modular ligation of conventional RAFT polymers.

Making light work of RAFT conjugation: a non-activated RAFT agent at the end of RAFT polymers can readily be coupled with ortho-quinodimethanes (photoenols) in a photo-triggered Diels-Alder reaction under mild conditions without catalyst. The method is universal and opens the door for the conjugation of a large number of RAFT-prepared polymers with photoenol-functionalized (macro)molecules. (RAFT=reversible addition-fragmentation chain transfer.).

Combinatorial solution-phase synthesis of (2S,4S)-4-acylamino-5-oxopyrrolidine-2-carboxamides.

Solution-phase combinatorial synthesis of (2S,4S)-4-acylamino-5-oxopyrrolidine-2-carboxamides was studied. First, di-tert-butyl (2S,4S)-4-amino-5-oxopyrrolidine-1,2-dicarboxylate hydrochloride was prepared as the key intermediate in five steps from (S)-pyroglutamic acid. Acylation of the amino group followed by acidolytic deprotection gave (2S,4S)-4-acylamino-5-oxopyrrolidine-2-carboxylic acids, which were then coupled with amines to furnish a library of (2S,4S)-4-acylamino-5-oxopyrrolidine-2-carboxamides. Four coupling reagents, BPC, EEDQ, TBTU, and PFTU, were tested for the amidation reactions in the final step. Amidations with EEDQ and TBTU led to the desired carboxamides. On the other hand, BPC and PFTU were not suited, since diketopiperazines were sometimes obtained instead of the desired carboxamides.