Ibrexafungerp: An orally active β-1,3-glucan synthesis inhibitor.

We previously reported medicinal chemistry efforts that identified MK-5204, an orally efficacious β-1,3-glucan synthesis inhibitor derived from the natural product enfumafungin. Further extensive optimization of the C2 triazole substituent identified 4-pyridyl as the preferred replacement for the carboxamide of MK-5204, leading to improvements in antifungal activity in the presence of serum, and increased oral exposure. Reoptimizing the aminoether at C3 in the presence of this newly discovered C2 substituent, confirmed that the (R) t-butyl, methyl aminoether of MK-5204 provided the best balance of these two key parameters, culminating in the discovery of ibrexafungerp, which is currently in phase III clinical trials.

MK-5204: An orally active β-1,3-glucan synthesis inhibitor.

Our previously reported efforts to produce an orally active β-1,3-glucan synthesis inhibitor through the semi-synthetic modification of enfumafungin focused on replacing the C2 acetoxy moiety with an aminotetrazole and the C3 glycoside with a N,N-dimethylaminoether moiety. This work details further optimization of the C2 heterocyclic substituent, which identified 3-carboxamide-1,2,4-triazole as a replacement for the aminotetrazole with comparable antifungal activity. Alkylation of either the carboxamidetriazole at C2 or the aminoether at C3 failed to significantly improve oral efficacy.

Efficacy of Relebactam (MK-7655) in Combination with Imipenem-Cilastatin in Murine Infection Models.

The World Health Organization has identified antimicrobial resistance as a global public health threat since the prevalence and spread of antibiotic resistance among bacterial pathogens worldwide are staggering. Carbapenems, such as imipenem and meropenem, have been used to treat multidrug-resistant bacteria; however, since the development of resistance to carbapenems, β-lactam antibiotics in combination with β-lactamase inhibitors (BLI) has been one of the most successful strategies to enhance the activity of β-lactam antibiotics. Relebactam (REL) is a new BLI which has been found to inhibit class A and class C β-lactamases REL has been reported to restore imipenem's activity against both imipenem-resistant and Reported here are the efficacy studies of the imipenem-cilastatin (IMI)-REL combination in mouse models of disseminated and pulmonary infection caused by imipenem-resistant clinical isolates of and The combination was also evaluated in a delayed pulmonary model of infection.

Discovery of Chromane Propionic Acid Analogues as Selective Agonists of GPR120 with Activity in Rodents.

GPR120 (FFAR4) is a fatty acid sensing G protein coupled receptor (GPCR) that has been identified as a target for possible treatment of type 2 diabetes. A selective activator of GPR120 containing a chromane scaffold has been designed, synthesized, and evaluated . Results of these efforts suggest that chromane propionic acid is a suitable tool molecule for further animal studies.

Design, Synthesis, and Evaluation of Novel and Selective G-protein Coupled Receptor 120 (GPR120) Spirocyclic Agonists.

Type 2 diabetes mellitus (T2DM) is an ever increasing worldwide epidemic, and the identification of safe and effective insulin sensitizers, absent of weight gain, has been a long-standing goal of diabetes research. G-protein coupled receptor 120 (GPR120) has recently emerged as a potential therapeutic target for treating T2DM. Natural occurring, and more recently, synthetic agonists have been associated with insulin sensitizing, anti-inflammatory, and fat metabolism effects.

Discovery and Optimization of a Novel Triazole Series of GPR142 Agonists for the Treatment of Type 2 Diabetes.

GPR142 has been identified as a potential glucose-stimulated insulin secretion (GSIS) target for the treatment of type 2 diabetes mellitus (T2DM). A class of triazole GPR142 agonists was discovered through a high throughput screen. The lead compound suffered from poor metabolic stability and poor solubility.

Discovery of benzofuran propanoic acid GPR120 agonists: From uHTS hit to mechanism-based pharmacodynamic effects.

The transformation of an aryloxybutanoic acid ultra high-throughput screening (uHTS) hit into a potent and selective series of G-protein coupled receptor 120 (GPR120) agonists is reported. uHTS hit 1 demonstrated an excellent rodent pharmacokinetic profile and selectivity over the related fatty acid receptor GPR40, but only modest GPR120 potency. Optimization of the "left-hand" aryl group led to compound 6, which demonstrated a GPR120 mechanism-based pharmacodynamic effect in a mouse oral glucose tolerance test (oGTT).

Scaffold-hopping from xanthines to tricyclic guanines: A case study of dipeptidyl peptidase 4 (DPP4) inhibitors.

Molecular modeling of unbound tricyclic guanine scaffolds indicated that they can serve as effective bioisosteric replacements of xanthines. This notion was further confirmed by a combination of X-ray crystallography and SAR studies, indicating that tricyclic guanine DPP4 inhibitors mimic the binding mode of xanthine inhibitors, exemplified by linagliptin. Realization of the bioisosteric relationship between these scaffolds potentially will lead to a wider application of cyclic guanines as xanthine replacements in drug discovery programs for a variety of biological targets.

Discovery of Novel Tricyclic Heterocycles as Potent and Selective DPP-4 Inhibitors for the Treatment of Type 2 Diabetes.

In our efforts to develop second generation DPP-4 inhibitors, we endeavored to identify distinct structures with long-acting (once weekly) potential. Taking advantage of X-ray cocrystal structures of sitagliptin and other DPP-4 inhibitors, such as alogliptin and linagliptin bound to DPP-4, and aided by molecular modeling, we designed several series of heterocyclic compounds as initial targets. During their synthesis, an unexpected chemical transformation provided a novel tricyclic scaffold that was beyond our original design.

Novel orally active inhibitors of β-1,3-glucan synthesis derived from enfumafungin.

The clinical success of the echinocandins, which can only be administered parentally, has validated β-1,3-glucan synthase (GS) as an antifungal target. Semi-synthetic modification of enfumafungin, a triterpene glycoside natural product, was performed with the aim of producing a new class of orally active GS inhibitors. Replacement of the C2 acetoxy moiety with various heterocycles did not improve GS or antifungal potency.

Elucidation of DnaE as the Antibacterial Target of the Natural Product, Nargenicin.

Resistance to existing classes of antibiotics drives the need for discovery of novel compounds with unique mechanisms of action. Nargenicin A1, a natural product with limited antibacterial spectrum, was rediscovered in a whole-cell antisense assay. Macromolecular labeling in both Staphylococcus aureus and an Escherichia coli tolC efflux mutant revealed selective inhibition of DNA replication not due to gyrase or topoisomerase IV inhibition.

Competition should open up savings.

Mark Powles, chief executive of Business Stream, which says it has helped Scottish businesses and public sector organisations save over £100 million on their water bills since retail competition in this area was introduced in Scotland in April 2008, explains how, thanks to legislation that came into effect earlier this year, NHS Trusts in England will, from April 2017, be able to benefit from similar 'full competition' in their choice of water supplier. Here he advises on some of the steps that healthcare estates teams and others responsible for their organization's water supply should be taking in preparation.

Broadening the spectrum of β-lactam antibiotics through inhibition of signal peptidase type I.

The resistance of methicillin-resistant Staphylococcus aureus (MRSA) to all β-lactam classes limits treatment options for serious infections involving this organism. Our goal is to discover new agents that restore the activity of β-lactams against MRSA, an approach that has led to the discovery of two classes of natural product antibiotics, a cyclic depsipeptide (krisynomycin) and a lipoglycopeptide (actinocarbasin), which potentiate the activity of imipenem against MRSA strain COL. We report here that these imipenem synergists are inhibitors of the bacterial type I signal peptidase SpsB, a serine protease that is required for the secretion of proteins that are exported through the Sec and Tat systems.

MK-4815, a potential new oral agent for treatment of malaria.

Malaria continues to have a significant impact on the health of the developing world. Efforts to combat this disease now focus on combination therapy in order to stem the emergence of resistant parasites. Continued efforts are needed to discover and develop new agents for use in combination antimalarial regimens.

Efficacy of caspofungin in a juvenile mouse model of central nervous system candidiasis.

Neonatal candidiasis is an increasingly common occurrence causing significant morbidity and mortality and a higher risk of dissemination to the central nervous system (CNS) than that seen with older patients. The current understanding of optimal antifungal therapy in this setting is limited. We have developed a model of disseminated candidiasis with CNS involvement in juvenile mice to assess the efficacy of the echinocandin caspofungin relative to amphotericin B (AmB).

Antidiabetic and antisteatotic effects of the selective fatty acid synthase (FAS) inhibitor platensimycin in mouse models of diabetes.

Platensimycin (PTM) is a recently discovered broad-spectrum antibiotic produced by Streptomyces platensis. It acts by selectively inhibiting the elongation-condensing enzyme FabF of the fatty acid biosynthesis pathway in bacteria. We report here that PTM is also a potent and highly selective inhibitor of mammalian fatty acid synthase.

Isolation and structure elucidation of parnafungins, antifungal natural products that inhibit mRNA polyadenylation.

The Candida albicans Fitness Test, a whole-cell screening platform, was used to profile crude fermentation extracts for novel antifungal natural products with interesting mechanisms of action. An extract with intrinsic antifungal activity from the fungus Fusarium larvarum displayed a Fitness Test profile that strongly implicated mRNA processing as the molecular target responsible for inhibition of fungal growth. Isolation of the active components from this sample identified a novel class of isoxazolidinone-containing natural products, which we have named parnafungins.

Characterization of Plasmodium falciparum cGMP-dependent protein kinase (PfPKG): antiparasitic activity of a PKG inhibitor.

Cyclic GMP-dependent protein kinase (PKG) has been biochemically and genetically validated in Toxoplasma gondii as a primary target responsible for the antiparasitic activity of the trisubstituted pyrrole 4-[2-(4-fluorophenyl)-5-(1-methylpiperidine-4-yl)-1H pyrrol-3-yl] pyridine (Compound 1) [Biftu T, Feng D, Ponpipom M, et al. Synthesis and SAR of 2,3-diarylpyrrole inhibitors of parasite cGMP-dependent protein kinase as novel anticoccidial agents. Bioorg Med Chem Lett 2005;15:3296-301; Gurnett AM, Liberator PA, Dulski PM, et al.

Potent 4-aminopiperidine based antimalarial agents.

A series of compounds with potent activity against a multi-drug-resistant strain of Plasmodium falciparum, the causative agent of the deadliest strain of malaria, is described. These compounds were also tested for cytotoxicity in human foreskin fibroblast assays, evaluated to determine their logD, and assayed for metabolism by human and murine hepatocytes. This work resulted in the development of compounds 9e and 10d, which showed good potency (IC(50)=75 nM and <60 nM, respectively, against Dd2), acceptable logD values, and reasonable metabolic stability.

Molecular phylogeny of the other tissue coccidia: Lankesterella and Caryospora.

Nearly complete sequences were obtained from the 18S rDNA genes of Eimeria falciformis (the type species of the genus), Caryospora bigenetica, and Lankesterella minima. Two clones of the rDNA gene from C. higenetica varied slightly in primary structure.

Efficacy of MK-991 (L-743,872), a semisynthetic pneumocandin, in murine models of Pneumocystis carinii.

In addition to its potent efficacy in animal models against Candida sp., Aspergillus fumigatus, and Histoplasma capsulatum, the clinical candidate pneumocandin MK-991 (formerly L-743,872) was also extremely potent against Pneumocystis carinii in models of immune-compromised animals. MK-991 was approximately 14 times more potent than the original natural product lead, pneumocandin B0.

New semisynthetic pneumocandins with improved efficacies against Pneumocystis carinii in the rat.

A new series of semisynthetic, water-soluble pneumocandin analogs has been found to be extremely potent against Pneumocystis carinii in an immunocompromised-rat model. These compounds are 5 to 10 times more potent than the parent natural product, pneumocandin B0 (L-688,786) (R. E.

Use of anti-CD4+ hybridoma cells to induce Pneumocystis carinii in mice.

A reduction of peripheral CD4+ cell levels has been correlated with the onset of Pneumocystis carinii pneumonia in AIDS patients. Most in vivo drug discovery and development for P. carinii have been conducted in corticosteroid-treated rats.

Use of beta-1,3-glucan-specific antibody to study the cyst wall of Pneumocystis carinii and effects of pneumocandin B0 analog L-733,560.

A new class of promising antipneumocystis agents, cyclic lipopeptide pneumocandin analogs, has been shown to effectively prevent Pneumocystis carinii cyst development in murine models. These compounds are believed to inhibit the biosynthesis of beta-1,3-glucan, a major constituent of the cell walls of various pathogenic fungi. However, all evidence of the presence of this polymer in P.