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The review paper entitled “The Essential Medicinal Chemistry of Curcumin”, published in the Journal of Medicinal Chemistry, by Nelson et al.1 is a well-designed paper, presenting a new (and negative) approach to the well-known biologically active compound; curcumin. Although some arguments throughout this paper are completely true, the approach of the authors is unfortunately far from impartial, and many of the conclusions the authors draw from some of their referred papers are especially hard to accept. On page 1621, line 11, the authors mention that the in vivo stability of curcumin is T1/2 < 5 min and F < 1% by referring to the research papers of Wang et al.2 and Yang et al.3 (refs 27 and 28 of the original paper). Interestingly, neither Wang nor Yang et al. directly report these values as the half-life of curcumin, which makes this a very biased supposition of the authors. The paper, published by Wang et al., reports the stability of curcumin in buffer solvents at laboratory conditions and in rat blood circulation. Since it is impossible to directly dissolve curcumin in water, curcumin was dissolved in methanol and then diluted with a buffer, and the amount of curcumin was measured in HPLC at different intervals. It is obvious that curcumin will start precipitating upon dilution with a buffer. Thus, it is doubtful that the sample injected in HPLC or administered to rats includes the supposed amount of curcumin. Yang et al. also do not report the half-life of curcumin below 5 min. This paper reports the elimination period as 28.1 ± 5.6 and 44.5 ± 7.5 min for 500 mg/kg, p.o. and 10 mg/kg, i.v. of curcumin, respectively. It is noteworthy that the half-life results are reported by the studies made in rats, not human studies. A rat weighing 400 g has a total blood volume of approximately 25.6 mL,4 and the human blood volume is approximately 5.5 L. The half-life measurements of the compound during blood circulation were made without considering the insolubility of curcumin in buffer solutions or the stability measurements in rat blood circulation and therefore do not accurately illustrate the fate of curcumin upon circulation within human blood. More interestingly, the authors acknowledge that the half-life of curcumin with pH 7.4 and 37 °C in human blood is 360−480 min in Supplemental Table 2 of ref 1. However, they report its stability as T1/2 < 5 min on page 1621, left column line 11.

Peptide-based analogues of the gut-derived incretin hormone, glucagon-like peptide 1 (GLP1), stimulate insulin secretion in a glucose-dependent manner. Currently marketed GLP1 receptor (GLP1R) agonists are safe and effective in the management of Type 2 diabetes but often offer only modest weight loss. This has prompted the search for safe and effective alternatives to enhance the weight loss component of these treatments. We have demonstrated that concomitant activation GLP1R and the glucagon receptor (GCGR) can improve glucose metabolism and provide superior weight loss when compared to selective GLP1R agonism in preclinical species. This paper will highlight chemistry structure-activity relationship optimization and summarize in vivo efficacy studies toward the discovery of a once daily balanced dual agonist

Scientists from around the world are studying the effects of microgravity and cosmic radiation via the “off-Earth” International Space Station (ISS) laboratory platform. The ISS has helped scientists make discoveries that go beyond the basic understanding of Earth. Over 300 medical experiments have been performed to date, with the goal of extending the knowledge gained for the benefit of humanity. This paper gives an overview of these numerous space medical findings, critically identifies challenges and gaps, and puts the achievements into perspective toward long-term space traveling and also adding benefits to our home planet. The medical contents are trifold structured, starting with the well-being of space travelers (astronaut health studies), followed by medical formulation research under space conditions, and then concluding with a blueprint for space pharmaceutical manufacturing. The review covers essential elements of our Earth-based pharmaceutical research such as drug discovery, drug and formulation stability, drug–organ interaction, drug disintegration/bioavailability/pharmacokinetics, pathogen virulence, genome mutation, and body’s resistance. The information compiles clinical, medicinal, biological, and chemical research as well as fundamentals and practical applications.

Anti-Wolbachia therapy has been identified as a viable treatment for combating filarial diseases. Phenotypic screening revealed a series of pyrazolopyrimidine hits with potent anti-Wolbachia activity. This paper focuses on the exploration of the SAR for this chemotype, with improvement of metabolic stability and solubility profiles using medicinal chemistry approaches. Organic synthesis has enabled functionalization of the pyrazolopyrimidine core at multiple positions, generating a library of compounds of which many analogues possess nanomolar activity against Wolbachia in vitro with improved DMPK parameters. A lead compound, 15f, was selected for in vivo pharmacokinetics (PK) profiling in mice. The combination of potent anti-Wolbachia activity in two in vitro assessments plus the exceptional oral PK profiles in mice puts this lead compound in a strong position for in vivo proof-of-concept pharmacodynamics studies and demonstrates the strong potential for further optimization and development of this series for treatment of filariasis in the future.

[Image: see text] In this paper, we report the design, synthesis, and biological evaluation of the first selective bromodomain and extra-terminal domain (BET) BD1 bromodomains of the PET radiotracer [(18)F]PB006. The standard compound PB006 showed high affinity and good selectivity toward BRD4 BD1 (K(d) = 100 nM and 29-fold selectively for BD1 over BD2) in an in vitro binding assay. PET imaging experiments in rodents were performed to evaluate the bioactivity of [(18)F]PB006 in vivo. A biodistribution study of [(18)F]PB006 in mice revealed high radiotracer uptake in peripheral tissues, such as liver and kidney, and moderate radiotracer uptake in the brain. Further blocking studies demonstrated the significant radioactivity decreasing (20–30% reduction compared with baseline) by pretreating unlabeled PB006 and JQ1, suggesting the high binding selectivity and specificity of [(18)F]PB006. Our study indicated that [(18)F]PB006 is a potent PET probe selectively targeting BET BD1, and further structural optimization of the radiotracer is still required to improve brain uptake to support neuroepigenetic imaging.

[Image: see text] Neuraminidase (NA) is an important target for current research on anti-influenza drugs. The acylhydrazone derivatives containing the −CONHN=CH– framework have been shown to have good NA inhibitory activity. In this paper, a series of novel acylhydrazone NA inhibitors (9a–9n) were designed and synthesized, and the inhibitory activities against NA were evaluated in vitro. The NA inhibition results showed that compound 9j has the most potent inhibitory activity (IC(50) = 0.6 μM) against NA, which is significantly lower than that of the positive control oseltamivir carboxylic acid (OSC) (IC(50) = 17.00 μM). Molecular docking analysis indicates that the acylhydrazone group plays an important role in compound 9j, which can bind well to the residues Arg371 and Arg292 in the S1 subsite of NA. The good potency of 9j may be also ascribed to the extending of morpholinyl ring into the 430-cavity. The results of this work may contribute to the development of more potent NA inhibitors to against mutant influenza viruses.

Alzheimer's disease was first described in 1906 by Alois Alzheimer, who observed plaques in the brain tissue from patients that suffered dementia. Alzheimer's disease is the most common form of dementia and accounts for over 50% of the cases identified each year. Alzheimer's disease affects over 5 million patients in the United States, is the sixth leading cause of death among Americans, and accounts for over 200 billion dollars lost in medical care. Over 15 million people are counted as unpaid caretakers of these patients, and this causes a great burden on our health system. There are currently only five approved treatments for Alzheimer's disease, and none of these are a cure. Despite intensive research efforts, it is still not known what causes the disease, and effective treatments are greatly needed. As a result, the Obama administration recently declared the search for a treatment a major national priority and has increased the funding for basic research and caregiver support with a promised 156 million dollar investment. To highlight the importance in this area, the editors of the Journal of Medicinal Chemistry, ACS Chemical Neurosciences, and ACS Medicinal Chemistry Letters (Gunda I. Georg, Shaomeng Wang, Craig Lindsley, and Dennis Liotta) announced the simultaneous publication of Special Issues on Alzheimer's disease to be published in November to coincide with Alzheimer's Disease Awareness month. Links to these special issues will also be made available online on a specific page dedicated to this Alzheimer's disease collection. I was asked to be a Guest Editor of the ACS Medicinal Chemistry Letters special issue and thoroughly enjoyed reading all of the high-level papers that were submitted for this journal. We accepted 11 papers for the final edition that highlight several potential new treatment options or some new tools for potentially discovering how the disease works. There are four basic areas of research that the papers cover that range from inhibitors of specific enzymes to novel approaches and also a description of a new imaging agent. Stamford et al. highlight the preparation of novel β-secretase (BACE) inhibitors that are active in in vivo models of plaque formation. The compounds described are nonpeptido mimietic inhibitors that are active in in vivo models of plaques formation. Kaller et al. also describe novel BACE inhibitors based upon amino-hydroxy-ethyl amine compounds that are active in in vivo models. Another enzyme target that has been studied over the past 10 years is γ-secretase. Many groups have described potent inhibitors of this enzyme, but few compounds have reached their potential in clinical studies, presumably due to side effects brought on by inhibition of the related enzyme Notch. Wu and colleagues describe a novel series of γ-secretase inhibitors that possess some selectivity over Notch, and one compound is reported to have advanced to clinical trials. Another approach toward affecting this pathway has been focused on discovering compounds that act as modulators of γ-secretase and therefore do not inhibit Notch processing of essential proteins. The paper by Fuller is very interesting in that it describes a novel series of γ-secretase modulators that are based upon glycoside inhibitor templates. The paper by Huang also describes a novel series of small molecule oxadiazine γ-secretase modulators. This journal's special issue also describes several other approaches toward modulating the effects of Alzheimer's disease. Liu and colleagues have taken a different approach and report in their paper a series of compounds that are bivalent ligands that target multiple pathways involved in the disease. Zhou describes a strategy toward targeting inflammation that might occur in the course of the disease and have identified some compounds that show potential in animal models. In their paper, Dang and co-workers report on a novel series of compounds that act as activators of the chymotrypsin-like activity of the proteasome and also serve to inhibit the deactivating effects of Aβ40/42 on the proteasome. Lysosomes are involved in the clearance of some of the products of protein processing that contribute to Alzheimer's disease. Viswanathan and colleagues have developed several nonpeptidic compounds that are lysosomal modulators of cathepsin activity and show promise in an in vivo model of assessing the accumulation of AD type proteins. The paper by Darras describes the preparation of a series of tri- and tetracyclic butyl-cholinesterase inhibitors (BChE) that possess selectivity over the related enzyme acetyl ChE. Shao and colleagues have developed N-methyl Lansoprazole as a novel PET imaging agent for Tau neurofibrillary tangles (NFT), and their paper outlines their approach and the successful use of this agent in imaging studies. Finally, a must read in this issue is the Viewpoint article written by Dr. Richard Hargreaves from Merck Research Laboratories. The article is interesting and covers many aspects of the past and ongoing research into Alzheimer's disease. I hope you find the articles in this journal and the sister journals very interesting to read and that they stimulate your interest in Alzheimer's disease, which would lead to progress in your own laboratories.

[Image: see text] Trypanosoma brucei (T. brucei) and Trypanosoma cruzi (T. cruzi) are causative agents of parasitic diseases known as human African trypanosomiasis and Chagas disease, respectively. Together, these diseases affect 68 million people around the world. Current treatments are unsatisfactory, frequently associated with intolerable side-effects, and generally inadequate in treating all stages of disease. In this paper, we report the discovery of N-ethylurea pyrazoles that potently and selectively inhibit the viability of T. brucei and T. cruzi. Sharp and logical SAR led to the identification of 54 as the best compound, with an in vitro IC(50) of 9 nM and 16 nM against T. b. brucei and T. cruzi, respectively. Compound 54 demonstrates favorable physicochemical properties and was efficacious in a murine model of Chagas disease, leading to undetectable parasitemia within 6 days when CYP metabolism was inhibited.

[Image: see text] SPPL2a (Signal Peptide Peptidase Like 2a) is an intramembrane aspartyl protease engaged in the function of B-cells and dendritic cells. Despite being an attractive target for modulation of the immune system, selective SPPL2a inhibitors are barely described in the literature. Recently, we have disclosed a selective, small molecular weight agent SPL-707 which confirmed that pharmacological inhibition of SPPL2a leads to the accumulation of its substrate CD74/p8 and as a consequence to a reduction in the number of B-cells as well as myeloid dendritic cells in mice. In this paper we describe the discovery of novel hydroxyethylamine based SPPL2a inhibitors. Starting from a rather lipophilic screening hit, several iterative optimization cycles allowed for its transformation into a highly potent and selective compound 15 (SPL-410) which inhibited in vivo CD74/p8 fragment processing in mice at 10 mg/kg oral dose.

[Image: see text] Increasing the success rate and throughput of drug discovery will require efficiency improvements throughout the process that is currently used in the pharmaceutical community, including the crucial step of identifying hit compounds to act as drivers for subsequent optimization. Hit identification can be carried out through large compound collection screening and often involves the generation and testing of many hypotheses based on available knowledge. In practice, hypothesis generation can involve the selection of promising chemical structures from compound collections using predictive models built from previous screening/assay results. Available physical collections, typically used during hit identification, are of the order of 10(6) compounds but represent only a small fraction of the small molecule drug-like chemical space. In an effort to survey a larger portion of chemical space and eliminate inefficiencies during hit identification, we introduce a new process, termed Idea2Data (I2D) that tightly integrates computational and experimental components of the drug discovery process. I2D provides the ability to connect a vast virtual collection of compounds readily synthesizable on automated synthesis systems with computational predictive models for the identification of promising structures. This new paradigm enables researchers to process billions of virtual molecules and select structures that can be prepared on automated systems and made available for biological testing, allowing for timely hypothesis testing and follow-up. Since its introduction, I2D has positively impacted several portfolio efforts through identification of new chemical scaffolds and functionalization of existing scaffolds. In this Innovations paper, we describe the I2D process and present an application for the discovery of new ULK inhibitors.

Anti-Wolbachia therapy has been identified as a viable treatment for combating filarial diseases. Phenotypic screening revealed a series of pyrazolopyrimidine hits with potent anti-Wolbachia activity. This paper focuses on the exploration of the SAR for this chemotype, with improvement of metabolic stability and solubility profiles using medicinal chemistry approaches. Organic synthesis has enabled functionalization of the pyrazolopyrimidine core at multiple positions, generating a library of compounds of which many analogues possess nanomolar activity against Wolbachia in vitro with improved DMPK parameters. A lead compound, 15f, was selected for in vivo pharmacokinetics (PK) profiling in mice. The combination of potent anti-Wolbachia activity in two in vitro assessments plus the exceptional oral PK profiles in mice puts this lead compound in a strong position for in vivo proof-of-concept pharmacodynamics studies and demonstrates the strong potential for further optimization and development of this series for treatment of filariasis in the future.

Biochemical assay interference is becoming increasingly recognized as a significant waste of resource in drug discovery, both in industry and academia. A seminal publication from Baell and Holloway raised the awareness of this issue, and they published a set of alerts to identify what they described as PAINS (pan-assay interference compounds). These alerts have been taken up by drug discovery groups, even though the original paper had a somewhat limited data set. Here, we have taken Lilly’s far larger internal data set to assess the PAINS alerts on four criteria: promiscuity (over six assay formats including AlphaScreen), compound stability, cytotoxicity, and presence of a high Hill slope as a surrogate for non-1:1 protein–ligand binding. It was found that only three of the alerts show pan-assay promiscuity, and the alerts appear to encode primarily AlphaScreen promiscuous molecules. Although not enriching for pan-assay promiscuity, many of the alerts do encode molecules that are unstable, show cytotoxicity, and increase the prevalence of high Hill slopes.

In order to find optimal core structures as starting points for lead optimization, a multiparameter lead generation workflow was designed with the goal of finding BACE-1 inhibitors as a treatment for Alzheimer's disease. De novo design of core fragments was connected with three predictive in silico models addressing target affinity, permeability, and hERG activity, in order to guide synthesis. Taking advantage of an additive SAR, the prioritized cores were decorated with a few, well-characterized substituents from known BACE-1 inhibitors in order to allow for core-to-core comparisons. Prediction methods and analyses of how physicochemical properties of the core structures correlate to in vitro data are described. The syntheses and in vitro data of the test compounds are reported in a separate paper by Ginman et al. [J. Med. Chem. 2013, 56, 4181-4205]. The affinity predictions are described in detail by Roos et al. [J. Chem. Inf. 2014, DOI: 10.1021/ci400374z].

Call for papers! ACS Medicinal Chemistry Letters is now accepting manuscript submissions for a special issue entitled “Allosteric Modulation of Ionotropic Glutamate Receptors”. This special issue is a cross-thematic issue with Journal of Medicinal Chemistry and ACS Chemical Neuroscience. The ACS Medicinal Chemistry Letters special issue is scheduled for publication in early 2019.

This paper characterizes N-benzyl-3-sulfonamidopyrrolidines (gyramides) as DNA gyrase inhibitors. Gyramide A was previously shown to exhibit antimicrobial activity that suggested it inhibited bacterial cell division. In this study, we conducted target identification studies and identified DNA gyrase as the primary target of gyramide A. The gyramide A resistance-determining region in DNA gyrase is adjacent to the DNA cleavage gate and is a new site for inhibitor design. We studied the antibiotic effects of gyramides A-C in combination with the Gram-negative efflux pump inhibitor MC-207,110 (60 μM). The gyramides had a minimum inhibitory concentration of 10-40 μM against Escherichia coli, Pseudomonas aeruginosa, Salmonella enterica, Staphylococcus aureus, and Streptococcus pneumoniae; the compounds were ineffective against Enterococcus faecalis. The IC(50) of gyramides A-C against E. coli DNA gyrase was 0.7- 3.3 μM. The N-benzyl-3-sulfonamidopyrrolidines described in this manuscript represent a starting point for development of antibiotics that bind a new site in DNA gyrase.

In this paper we describe a series of 3-cyano-5-aryl-7-aminopyrazolo[1,5-a]pyrimidine hits identified by kinase-focused subset screening as starting points for the structure-based design of conformationally constrained 6-acetamido-indole inhibitors of CK2. The synthesis, SAR, and effects of this novel series on Akt signaling and cell proliferation in vitro are described.

Integration of human immunodeficiency virus type 1 DNA into an infected cell genome is one of the key steps of the viral replication cycle. Therefore, viral enzyme integrase, which realizes the integration, represents an attractive and validated target for the development of new antiviral drugs. In this paper, the anti-integrase activity of a series of conjugates of single-stranded oligonucleotides with hydrophobic molecules was tested, and the structure-activity relationships were also analyzed. Both oligonucleotide and hydrophobic parts of the conjugates influenced the inhibitory potency. Conjugates of 11-mer phosphorothioate oligonucleotides with 6-carboxy-4,7,2',4',5',7'-hexachlorofluorescein (HEX) were found to be the most efficient inhibitors (IC50 = 20 nM) and might be considered as lead compounds for further development of integrase inhibitors.

The authors retract the article entitled “Novel 2-Aminobenzamides as Potential Orally Active Antithrombotic Agents” published in ACS Medicinal Chemistry Letters, 2013, 4, 32–36 (DOI: 10.1021/ml300217f) due to the confirmed scientific misconduct of Mr. Amit Verma. Based on the results of investigation of a committee established by The Head, Pharmacy Department, Faculty of Technology and Engineering, The M. S. University of Baroda, Vadodara, the authors conclude that some of the biological experiments represented in the Letter are not reproducible due to manipulation and/or misrepresentation by Mr. Amit Verma. Therefore, all authors agreed on retraction of this paper.

We synthesized compounds 1a–1m and 2a–2h according to the synthetic procedure reported by Younis Baqi and Christa E. Muller. We added the related two papers as references in the Supporting Information and sentences “Compounds 1a–1m were synthesized according to synthetic procedure1,2″ and “Compounds 2a–2h were synthesized according to synthetic procedure1,2″ were also added before the related experimental procedures.