Farnesyl pyrophosphate synthase (FPPS) is an established target for the treatment of bone diseases, but also shows promise as an anticancer and anti-infective drug target. Currently available anti-FPPS drugs are active-site-directed bisphosphonate inhibitors, the peculiar pharmacological profile of which is inadequate for therapeutic indications beyond bone diseases. The recent discovery of an allosteric binding site has paved the way toward the development of novel non-bisphosphonate FPPS inhibitors with broader therapeutic potential, notably as immunomodulators in oncology. Herein we report the discovery, by an integrated lead finding approach, of two new chemical classes of allosteric FPPS inhibitors that belong to the salicylic acid and quinoline chemotypes. We present their synthesis, biochemical and cellular activities, structure-activity relationships, and provide X-ray structures of several representative FPPS complexes. These novel allosteric FPPS inhibitors are devoid of any affinity for bone mineral and could serve as leads to evaluate their potential in none-bone diseases.
A small library of fragments comprising putative recognition motifs for the catalytic dyad of aspartic proteases was generated by in silico similarity searches within the corporate compound deck based on rh-renin active site docking and scoring filters. Subsequent screening by NMR identified the low-affinity hits 3 and 4 as competitive active site binders, which could be shown by X-ray crystallography to bind to the hydrophobic S3-S1 pocket of rh-renin. As part of a parallel multiple hit-finding approach, the 3,5-disubstituted piperidine (rac)-5 was discovered by HTS using a enzymatic assay. X-ray crystallography demonstrated the eutomer (3S,5R)-5 to be a peptidomimetic inhibitor binding to a nonsubstrate topography of the rh-renin prime site. The design of the potent and selective (3S,5R)-12 bearing a P3(sp)-tethered tricyclic P3-P1 pharmacophore derived from 3 is described. (3S,5R)-12 showed oral bioavailability in rats and demonstrated blood pressure lowering activity in the double-transgenic rat model.
A screening method to evaluate Suzuki− Miyaura and Buchwald−Hartwig coupling reactions under aqueous surfactant conditions has been established, leading to high yielding and highly selective Suzuki− Miyaura and Buchwald−Hartwig reactions under mild reaction temperatures and ecologically improved conditions. The screening method highlighted the utility of Buchwald−Hartwig third generation precatalysts for unprecedented high conversion Buchwald−Hartwig C− N coupling reactions in water.
Targeting drugs to their desired site of action can increase their safety and efficacy. Bisphosphonates are prototypical examples of drugs targeted to bone. However, bisphosphonate bone affinity is often considered too strong and cannot be significantly modulated without losing activity on the enzymatic target, farnesyl pyrophosphate synthase (FPPS). Furthermore, bisphosphonate bone affinity comes at the expense of very low and variable oral bioavailability. FPPS inhibitors were developed with a monophosphonate as a bone-affinity tag that confers moderate affinity to bone, which can furthermore be tuned to the desired level, and the relationship between structure and bone affinity was evaluated by using an NMR-based bone-binding assay. The concept of targeting drugs to bone with moderate affinity, while retaining oral bioavailability, has broad application to a variety of other bone-targeted drugs.
3,5-Disubstituted
piperidines are versatile building blocks that
find broad application in medicinal chemistry programs. Here we describe
how all four diastereoisomers of a 5-aryl-substituted nipecotic acid
derivative were prepared on preparative scale in high enantiomeric
purity. The piperidine core structure was formed by catalytic hydrogenation
of the corresponding pyridine derivatives. After Boc-protection, the
resulting cis/trans mixture was
separated by preparative normal phase chromatography into the pure cis and pure trans racemates. Subsequent
preparative separation of those racemates by Simulated Moving Bed
chromatography (SMB) allowed us to obtain all four enantiopure isomers
in amounts between 80 and 140 g. The absolute configuration of all
compounds was determined by crystallization and X-ray spectroscopy
of suitable derivatives.
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