Discovery of CVN636: A Highly Potent, Selective, and CNS Penetrant mGluR7 Allosteric Agonist.

The low affinity metabotropic glutamate receptor mGluR7 has been implicated in numerous CNS disorders; however, a paucity of potent and selective activators has hampered full delineation of the functional role and therapeutic potential of this receptor. In this work, we present the identification, optimization, and characterization of highly potent, novel mGluR7 agonists. Of particular interest is the chromane CVN636, a potent (EC50 7 nM) allosteric agonist which demonstrates exquisite selectivity for mGluR7 compared to not only other mGluRs, but also a broad range of targets. CVN636 demonstrated CNS penetrance and efficacy in an in vivo rodent model of alcohol use disorder. CVN636 thus has potential to progress as a drug candidate in CNS disorders involving mGluR7 and glutamatergic dysfunction.

1,2,4-Triazolo-[1,5-a]pyridine HIF Prolylhydroxylase Domain-1 (PHD-1) Inhibitors With a Novel Monodentate Binding Interaction.

Herein we describe the identification of 4-{[1,2,4]triazolo[1,5-a]pyridin-5-yl}benzonitrile-based inhibitors of the hypoxia-inducible factor prolylhydroxylase domain-1 (PHD-1) enzyme. These inhibitors were shown to possess a novel binding mode by X-ray crystallography, in which the triazolo N1 atom coordinates in a hitherto unreported monodentate interaction with the active site Fe2+ ion, while the benzonitrile group accepts a hydrogen-bonding interaction from the side chain residue of Asn315. Further optimization led to potent PHD-1 inhibitors with good physicochemical and pharmacokinetic properties.

Assessing molecular scaffolds for CNS drug discovery.

There is a need for high-quality screening collections that maximise hit rate and minimise the time taken in lead optimisation to derive a candidate drug. Identifying and accessing molecules that meet these criteria is a challenge. Within central nervous system (CNS)-focused drug discovery, this challenge is heightened by the requirement for lead compounds to cross the blood-brain barrier. Herein, we demonstrate use of a multiparameter optimisation tool to prioritise the synthesis of molecular scaffolds that, when subsequently decorated, yield screening compounds with experimentally determined properties that align with CNS lead generation needs. Prospective use of this CNS Lead Multiparameter Optimisation (MPO) scoring protocol can guide the further development of novel synthetic methodologies to access CNS-relevant and lead-like chemical space.

Peptidomimetic inhibitors of bacterial peptide deformylase.

A series of N-formyl hydroxylamine peptide deformylase inhibitors containing a cyclic azaamino acid moiety between the P1' and P3' substituents are presented. Selected compounds display antibacterial activity against pathogens associated with respiratory tract infections with representative compounds showing excellent MICs against Haemophilus influenzae.

CHR-2797: an antiproliferative aminopeptidase inhibitor that leads to amino acid deprivation in human leukemic cells.

CHR-2797 is a novel metalloenzyme inhibitor that is converted into a pharmacologically active acid product (CHR-79888) inside cells. CHR-79888 is a potent inhibitor of a number of intracellular aminopeptidases, including leucine aminopeptidase. CHR-2797 exerts antiproliferative effects against a range of tumor cell lines in vitro and in vivo and shows selectivity for transformed over nontransformed cells. Its antiproliferative effects are at least 300 times more potent than the prototypical aminopeptidase inhibitor, bestatin. However, the mechanism by which inhibition of these enzymes leads to proliferative changes is not understood. Gene expression microarrays were used to profile changes in mRNA expression levels in the human promyelocytic leukemia cell line HL-60 treated with CHR-2797. This analysis showed that CHR-2797 treatment induced a transcriptional response indicative of amino acid depletion, the amino acid deprivation response, which involves up-regulation of amino acid synthetic genes, transporters, and tRNA synthetases. These changes were confirmed in other leukemic cell lines sensitive to the antiproliferative effects of CHR-2797. Furthermore, CHR-2797 treatment inhibited phosphorylation of mTOR substrates and reduced protein synthesis in HL-60 cells, both also indicative of amino acid depletion. Treatment with CHR-2797 led to an increase in the concentration of intracellular small peptides, the substrates of aminopeptidases. It is suggested that aminopeptidase inhibitors, such as CHR-2797 and bestatin, deplete sensitive tumor cells of amino acids by blocking protein recycling, and this generates an antiproliferative effect. CHR-2797 is orally bioavailable and currently undergoing phase II clinical investigation in the treatment of myeloid leukemia.

Synthesis of a simplified analogue of eleutherobin via a Claisen rearrangement and ring closing metathesis strategy.

The enantioselective synthesis of a simplified eleutherobin analogue by ring closing metathesis (RCM) of the 2,9-divinyl-substituted tetrahydro-oxonin is described; the analogue and an advanced intermediate revealed microtubule stabilising properties in the micromolar range.

Structure-activity relationships of the peptide deformylase inhibitor BB-3497: modification of the methylene spacer and the P1' side chain.

Structural modifications to the peptide deformylase inhibitor BB-3497 are described. In this paper, we describe the initial SAR around this lead for modifications to the methylene spacer and the P1' side chain. Enzyme inhibition and antibacterial activity data revealed that the optimum distance between the N-formyl hydroxylamine metal binding group and the P1' side chain is one unsubstituted methylene unit. Additionally, lipophilic P1' side chains that closely mimic the methionine residue in the substrate provided compounds with the best microbiological profile.

Structure--activity relationships of the peptide deformylase inhibitor BB-3497: modification of the P2' and P3' side chains.

Structural modifications to the peptide deformylase inhibitor BB-3497 are described. In this paper, we describe the initial SAR around this lead for modifications to both the P2' and P3' side chains. Enzyme inhibition and antibacterial activity data revealed that a variety of substituents are tolerated at the P2' and P3' positions of the inhibitor backbone. The data from this study highlights the potential for modification at the P2' and P3' positions to optimise the physicochemical properties.