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[Image: see text] The discovery of new targets for the treatment of malaria, in particular those aimed at the pre-erythrocytic stage in the life cycle, advanced with the demonstration that orally administered inhibitors of Plasmodium falciparum cGMP-dependent protein kinase (PfPKG) could clear infection in a murine model. This enthusiasm was tempered by unsatisfactory safety and/or pharmacokinetic issues found with these chemotypes. To address the urgent need for new scaffolds, this paper presents initial structure–activity relationships in an imidazole scaffold at four positions, representative in vitro ADME, hERG characterization, and cell-based antiparasitic activity. This series of PfPKG inhibitors has good in vitro PfPKG potency, low hERG activity, and cell-based antiparasitic activity against multiple Plasmodium species that appears to be correlated with the in vitro potency.

In recent years, understanding ways to improve the value and impact of heterocycles, in drug discovery and medicinal chemistry has increased with understanding of the multitude ways this fragment can influence properties. This chapter defines heterocycles as aromatic and non-aromatic rings containing one or more non-carbon atoms. Accompanying this is an expansion of the routes for synthesis that can be applied generally and more specifically to individual examples to efficiently deliver key building blocks used in drug discovery. This chapter will highlight recent examples of applications of heterocycles to favorably improve drug candidates in a range of therapeutic areas. In addition, synthetic methodology to access these heterocycles, including a discussion of late stage functionalization as a means to create new molecules will be presented.

The cGMP-dependent protein kinase in Plasmodium falciparum (PfPKG) plays multiple roles in the life cycle of the parasite. As a result, this enzyme is a potential target for new antimalarial agents. Existing inhbitors, while potent and active in malaria models are not optimal. This communication describes initial optimization of a structurally distinct class of PfPKG inhibitors.

[Image: see text] Lymphatic filariasis infects over 120 million people worldwide and can lead to significant disfigurement and disease. Resistance is emerging with current treatments, and these therapies have dose limiting adverse events; consequently new targets are needed. One approach to achieve this goal is inhibition of parasitic protein kinases involved in circumventing host defense mechanisms. This report describes structure–activity relationships leading to the identification of a potent, orally bioavailable stress activated protein kinase inhibitor that may be used to investigate this hypothesis.

Conformational restriction is a useful approach for ligand design in organic and medicinal chemistry. This manuscript reports the facile synthesis and in silico conformational analysis of two new diastereomeric [3.2.2]-3-azabicyclic, two new [3.2.1]-3-aza-8-oxy-bicyclic and one new [3.2.1]-3-azabicyclic diamine scaffolds. A conformational analysis of these structures along with calculation of carbon–carbon/carbon–nitrogen bond angles was carried out and compared to those in the flexible 1,3-diaminopropane template upon which they were based. It is of particular importance that these scaffolds have bond lengths and angles that can overlap with low energy conformers of the flexible diamine. Such information is useful for ligand design in organic chemistry and for development of structure activity relationships and in silico screening in medicinal chemistry.

The discovery and clinical development of heat shock protein 90 (Hsp90) inhibitors continue to progress. A number of Hsp90 inhibitors are in clinical trials, and preclinical discoveries of new chemotypes that bind to distinct regions in the protein as well as isoform selective compounds are active areas of research. This review will highlight progress in the field since 2010.

Protein kinases are becoming widely investigated targets for treatment of protozoal parasitic tropical diseases such as malaria and leishmaniasis. The search for potent, selective inhibitors of these parasitic enzymes has been aided by the extensive variety of structures prepared for human diseases. Genomic approaches to target identification and validation have aided the search. Substantial progress has been made and research is continuing to expand in an effort to find safe, effective drug candidates for these difficult to treat and widespread diseases.

Small molecules remain the backbone for modern drug discovery. They are conceived and synthesized by medicinal chemists, many of whom were originally trained as organic chemists. Support from government and industry to provide training and personnel for continued development of this critical skill set has been declining for many years. This Viewpoint highlights the value of organic chemistry and organic medicinal chemists in the complex journey of drug discovery as a reminder that basic science support must be restored.

Drug discovery for non-life-threatening disorders is an active area of medicinal chemistry research. This chapter will describe the discovery and properties of phosphodiesterase 5 inhibitors for erectile dysfunction, the medicinal chemistry of agents for treatment of insomnia, and smoking cessation. Keywords: insomnia; phosphodiesterase 5 inhibitors; smoking cessation

The synthesis and structure–activity relationships of novel dipeptidyl peptidase IV inhibitors replacing the classical cyanopyrrolidine P1 group with other small nitrogen heterocycles are described. A unique potency enhancement was achieved with β-branched natural and unnatural amino acids, particularly adamantylglycines, linked to a (2S,3R)-2,3-methanopyrrolidine based scaffold.

Phosphodiesterase enzymes convert cyclic GMP and cyclic AMP to the corresponding nucleotide monophosphates. Phosphodiesterase 5 (PDE5) inhibition is now a widely accepted and efficacious therapeutic option for the treatment of erectile dysfunction in men, as a result of extensive clinical experience with sildenafil and other new PDE5 inhibitors. Research in the field continues at a substantial level to identify new, selective PDE5 inhibitors and to investigate their usefulness and activity in other areas. This review summarizes recent clinical trials with PDE5 inhibitors, advances in medicinal chemistry, and other activities and potential applications of this class of compounds.

International audience; Preventing viral entry into cells is a recognized approach for HIV therapy and has attracted attention for use against the hepatitis C virus (HCV). Recent reports described the activity of (−)-epigallocatechin gallate (EGCG) as an inhibitor of HCV entry with modest potency. EGCG is a polyphenolic natural product with a wide range of biological activity and unfavorable pharmaceutical properties. In an attempt to identify more drug-like EGCG derivatives with improved efficacy as HCV entry inhibitors, we initiated structure–activity investigations using semi-synthetic and synthetic EGCG analogs. The data show that there are multiple regions in the EGCG structure that contribute to activity. The gallate ester portion of the molecule appears to be of particular importance as a 3,4-difluoro analog of EGCG enhanced potency. This derivative and other active compounds were shown not to be cytotoxic in Huh-7 cell culture. These data suggest that more potent, non-cytotoxic EGCG analogs can be prepared in an attempt to identify more drug-like candidates to treat HCV infection by this mechanism.

Summary: This application claims a series of indoles as molecules that inhibit tau phosphorylation. This approach to neurodegenerative disease is of interest because of the hypothesized role for tau in neuronal cell death. Tau is an intracellular protein that stabilizes microtubules and helps regulate their function, for example in cell division. Test compounds were studied for their ability to inhibit tau phosphorylation or inhibit α-synuclein in animals and in cell culture.

(-)-Epigallocatechin gallate (EGCG) is the major flavonoid of green tea and has been widely explored for a range of biological activities including anti-infective, anti-inflammatory, anti-cancer, and neuroprotection. Existing structure-activity data for EGCG has been largely limited to exploration of simple ethers and hydroxyl deletion. EGCG has poor drug-like properties because of multiple phenolic hydroxyl moieties and a metabolically labile ester. This work reports a substantial expansion of structure-activity understanding by exploring a range of semi-synthetic and synthetic derivatives with ester replacements and variously substituted aromatic and alicyclic groups containing more drug-like substituents. Structure-activity relationships for these molecules were obtained for Hsp90 inhibition. The results indicate that amide and sulfonamide linkers are suitable ester replacements. Hydroxylated aromatic rings and the cis-stereochemistry in EGCG are not essential for Hsp90 inhibition. Selected analogs in this series are more potent than EGCG in a luciferase refolding assay for Hsp90 activity.

Phosphodiesterase type 5 (PDE5) inhibitors with improved PDE isozyme selectivity relative to sildenafil may result in agents for the treatment of male erectile dysfunction (MED) with a lower incidence of PDE-associated adverse effects. This paper describes the discovery of 14, a PDE5 inhibitor with improved potency and selectivity in vitro compared to sildenafil. This compound shows activity in a functional assay of erectile function comparable to that of sildenafil.

A series of 3,9 disubstituted [(alkylthio)methyl]- and (alkoxymethyl)-K-252a derivatives was synthesized with the aim of enhancing and separating the neurotrophic properties from the undesirable NGF (trk A kinase) and PKC inhibitory activities of K-252a. Data from this series reveal that substitution in the 3- and 9-positions of K-252a with these groups reduces trk A kinase inhibitory properties approximately 100- to500-fold while maintaining or in certain cases enhancing the neurotrophic activity. From this research, 3,9-bis[(ethylthio)methyl]-K-252a (8) was identified as a potent and selective neurotrophic agent in vitro as measured by enhancement of choline acetyltransferase activity in embryonic rat spinal cord and basal forebrain cultures. Compound 8 was found to have weak kinase inhibitory activity for trk A, protein kinase C1 protein kinase A, and myosin light chain kinase. On the basis of the in vitro profile, 8 was evaluated in in vivo models suggestive of neurological diseases. Compound 8 was active in preventing degeneration of cholinergic neurons of the nucleus basalis magnocellularis (NBM) and reduced developmentally programmed cell death (PCD) of female rat spinal nucleus of the bulbocavernosus motoneurons and embryonic chick lumbar motoneurons.

Boceprevir was the first direct acting agent developed for the treatment of hepatitis C virus infection. Boceprevir functions by targeting NS3 protease, a viral enzyme essential for replication. This peptidomimetic molecule was optimized from a peptide lead to provide a potent, selective and orally bioavailable drug that can be combined with ribavirin and peg interferon to achieve sustained viral response (undetectable HCV RNA levels for 24 weeks after completion of therapy) in patients infected with Genotype 1 of the virus.This article provides a review of the pre-clinical and clinical discovery of boceprevir. This review includes the role and function of its molecular target, NS3 protease, as well as the assays used to measure in vitro efficacy, compound optimization and clinical studies to demonstrate safety and efficacy.As the first direct acting anti-HCV agent, boceprevir represents an important advance in therapy of this widespread chronic disease. Yet, while this therapy is a valuable approach, it does have limitations. Studies have suggested that 30% of patients do not achieve sustained viral response and 11% of patients have developed anemia and/or neutropenia. Current drug discovery and development efforts are underway to develop novel therapeutic options that address these issues.

Notes The authors declare no competing financial interest. Title: Gamma Secretase Modulators Application Number: WO 2013066740A1 Publication date: 10 May 2013 Priority Application: 61/553,384 Priority date: 31 October 2011 Inventors: W. Greenlee, D. Pissarnitski, Z. Zhao, Z. Zhu Assignee Company: Merck Sharpe & Dohme Disease Area: Neurodegeneration Biological Target: Gamma secretase Summary: Gamma secretase is an aspartic protease complex involved in the biosynthesis of Aβ peptide, a potential neurotoxic contributor in the progression of Alzheimer’s disease. Direct inhibition of enzymatic activity introduces potential selectivity issues associated with other biological functions of gamma secretase including Notch and Eph processing. As an alternative approach to gamma secretase inhibition, modulation of enzyme activity using, e.g., NSAIDs is a potentially druggable concept. This patent describes the synthesis and evaluation of a novel chemical series that demonstrates inhibition of gamma secretase activity in vitro and reduction of Aβ42 CSF levels following oral administration of a standard dose of 30 mg/kg. Primary Markush

Pyrrolo[3,4-c]carbazole derivatives were prepared as potential neurotrophic agents. The compounds were assayed for their ability to stimulate choline acetyltransferase (ChAT) activity in embryonic rat spinal cord cultures. These simplified K252a derivatives, although less potent and efficacious, have led to the identification of minimal structural requirements for K252a neurotrophic activity.

Ophiobolin A [1], 3-anhydroophiobolin A [2], ophiobolin B [3], and ophiobolin L [4] were isolated from fermentation broths of Cochliobolus heterostrophus. Preliminary screening showed that a number of organisms were capable of metabolizing the sesterterpene ophiobolin A [1]. Large-scale transformations of ophiobolin A [1] with Polyangium cellulosum produced 6 and 7 while Pseudomonas aeruginosa produced 8. Resting-cell preparations of Penicillium patulum afforded 9 and 10. The structures of these metabolites were established by spectroscopic methods and by comparison of the spectral data with those of the starting material. The antimicrobial activity of the ophiobolins was also evaluated.

A dihydroquinolinone moiety was found to be a potent serotonin reuptake inhibitor pharmacophore when combined with certain amines. This fragment was coupled with selected D2 ligands to prepare a series of dual acting compounds with attractive in vitro profiles as dopamine D2 partial agonists and serotonin reuptake inhibitors. Structure–activity studies revealed that the linker plays a key role in contributing to D2 affinity, function, and SRI activity.

A 5-fluoro-tetrahydrocarbazole serotonin reuptake inhibitor (SRI) building block was combined with a variety of linkers and dopamine D2 receptor ligands in an attempt to identify potent D2 partial agonist/SRI molecules for treatment of schizophrenia. This approach has the potential to treat a broader range of symptoms compared to existing therapies. Selected compounds in this series demonstrate high affinity for both targets and D2 partial agonism in cell-based and in vivo assays.

A structure-activity relationship study of the amine portion of the calcilytic compound NPS-2143 resulted in the discovery of substituted 2-benzylpyrrolidines as replacements for the 1,1-dimethyl-2-naphthalen-2-yl-ethylamine. When compared to NPS-2143, a newly discovered compound, 3h, exhibited similar potency as a calcium-sensing receptor (CaR) antagonist and a superior human ether-a-go-go related gene (hERG) profile.

The first 11 years of this millennium have been tumultuous for the science of and scientists engaged in drug discovery research. At a fundamental level, the need to more clearly link drug–target interactions to the molecular/cellular pathways in a disease process, furnish preclinical models that more accurately reproduce the human disease, and identify useful markers to monitor therapeutic effect have stimulated a research in the field of translational medicine. These tools and the science associated with them are intended to provide greater confidence in targets selected for prosecution. Pharmaceutical companies of all sizes are in various stages of implementation of this strategy in an effort to increase the likelihood of clinical success for their drug candidates. The beneficial impact of this revised discovery paradigm has yet to be fully felt in terms of improved rates of new drug approval. In pharmaceutical research, the influence has been dramatic in terms of new science that must be developed to support a given project. After approximately 6 years, this approach can also be evaluated for possible unforeseen or unanticipated negative effects to gain a more complete perspective on the net long-term value. For example, how much have these translational criteria contributed to several large pharmaceutical companies withdrawal from areas of research including CNS, hypertension, gastrointestinal diseases, osteoporosis, and asthma? A narrower spectrum of disease areas requires fewer scientists to conduct research. If one couples this with significant outsourcing of various components of the drug discovery process, a substantial headcount reduction in discovery organizations in both large and small companies has occurred. This hypothesis does not minimize the role that other well-publicized factors such as the increasing cost of drug discovery, revenue lost to generic competition, and increased emphasis on biologics play in the attempt to create leaner, more focused research organizations in companies of all sizes. In spite of this substantial downsizing, long-term benefits to drug discovery research are likely to emerge. Many excellent scientists are now engaged in new venues that include virtual companies, research foundations, and academic drug discovery centers. Pharmaceutical companies of all sizes are actively engaging external organizations to take advantage of specific expertise and technology lacking in their portfolios. Industrial scientists now in the academic world are using their valuable skills and irreplaceable experience to develop their own research interests and train the next generation of drug discovery scientists. No longer bound by rigid productivity targets, research priorities and ever-changing philosophies, creative ideas flourish and develop. This increased freedom allows scientists to reinforce the meaning and value of research in the context of drug discovery. Research by definition is “an investigation or experimentation aimed at the discovery and interpretation of facts, revision of accepted theories or laws in the light of new facts, or practical application of such new or revised theories or laws to explore the unknown.”1 Drug discovery in the pharmaceutical industry is and will remain a research-based endeavor. Everyone recognizes that there is no guarantee of success, that is, regulatory agency approval of a drug candidate for human use. More importantly, even with a solid translational foundation, there is no clear path to improving the number of candidates that progress from discovery through the clinic, regardless of the criteria used to vet and evaluate programs. One does not have to look far to recognize important contributions from academic drug discovery research. Professors Rick Silverman, Ted Taylor, Arun Ghosh, Dennis Liotta, and Robert Vince are well-known examples of academicians whose laboratories produced drugs. In each case, drug discovery research evolved from an ongoing program in the laboratory. Envoy Therapeutics, Aileron Therapeutics, Proteostasis Therapeutics, and FoldRx are just a few recent examples of companies based on research initiated in academic laboratories. Vanderbilt University recently established a drug discovery center focused on neuroscience targets, led by a group of experienced industrial scientists who also serve as faculty members. This group established multiple collaborations with pharmaceutical companies and advanced compounds into clinical testing. A number of other universities have drug discovery centers including the University of Pittsburgh, Temple University, University of North Carolina, Medical University of South Carolina, Yale, University of Illinois, Northeastern University, University of California at San Francisco, University of Kansas, University of Minnesota, and Montclair State University. Each center possesses unique attributes and capabilities, from specialized therapeutic/biology area interest (e.g., cancer, anti-infectives) to more diverse capabilities including medicinal chemistry, high-throughput screening, in vivo pharmacology, and pharmacokinetics. Many of these centers have ongoing collaborations based on a fit between the needs of an industrial partner and the capabilities and expertise of the academic group. Significant investments are being made in terms of modern research space, equipment, and personnel in an effort to strengthen these capabilities. In a survey of academic drug discovery carried out by Frye and co-workers at the University of North Carolina,2 three key obstacles to the ability of these centers to have an impact on drug discovery were identified as follows: funding, medicinal chemistry expertise, and lack of understanding of drug discovery in academia. Finances at these centers should be less of an obstacle in the future, assuming partnerships expand in number and value, and achieve milestones as specified in agreements. The influx of accomplished medicinal chemists and other drug discovery scientists into these academic centers will (and may have already begun to) address the latter two issues. However, the effect of these individuals will take time to be recognized and to impact existing perceptions by industrial partners. For example, experienced industrial scientists know that the activity of a novel compound in an animal model does not mean that one has an IND candidate in hand, regardless of how well this molecule performs relative to a positive control. Data on safety, pharmacokinetics, process chemistry, and even a more comprehensive structure–activity understanding are often lacking. Going forward, successful collaborations will be measured initially by the number of clinical candidates and much later by approvable NDAs, and it will be interesting to compare this portion of the industry's portfolio with internally derived programs. An issue that the Frye report did not discuss (and may not have addressed) is centered on intellectual property and the value of technology and discoveries. There is a natural division of needs in this regard. University scientists, particularly untenured and research faculty, want to publish their work, and industrial scientists need to protect their discoveries. Resolution of this dichotomy exceeds the Wisdom of Solomon. From personal experience and based on discussions with colleagues at many companies, nearly every university believes its contribution is much more valuable than the industrial partner's initial offer. The industrial concern will assume the vast majority of the expense and effort, especially if the project or technology moves into the clinic. This often translates into single-digit royalty payments to the academic institution and/or investigator. Universities must recognize that project- or technology-based collaborations are considered components in a research portfolio by the industrial partner. The value of each collaborative agreement will vary depending on its scope and importance as viewed by the industrial concern. Each partner must protect itself and its contribution to the joint effort, and as individuals on each side become more accustomed to dealing with these issues, the process is likely to become more streamlined and straightforward. The longer term benefits of industrial–academic collaboration in drug discovery research include the emergence of a new generation of scientists whose experience in an industrial–academic collaboration includes real-world exposure to science that impacts human health. Interactions between current and former industrial scientists, graduate students, and postdoctorals during these collaborations will furnish students with benefits beyond scientific learning to include teamwork, communication, and strategic-planning skills. It appears clear that the pharmaceutical industry will continue to expand its search for external partners to augment its strength, which lies in the later stages of the project. University-based drug discovery centers and faculties are increasing the number of former industrial scientists on their staff. The presence of former industrial scientists as a part of these collaborations should make corporate partners more comfortable when dealing with external partners because of their shared experiences (and scars). Drug discovery research will benefit as a direct result of the proliferation of the many new branches established outside the boundaries of industry. I look forward to the opportunities this will provide and to the continued evolution of our discipline.

A previous report from these laboratories identified the N-3-benzylimidazoquinazolinone nucleus as a more selective PDE5 inhibitor template compared to the pyrazolopyrimidine of sildenafil. This paper describes in detail the structure-activity relationships of a set of sulfonamide analogues, several of which are both more potent and more selective PDE5 inhibitors in vitro than sildenafil. The synthesis, in vitro enzyme activity and selectivity, and in vitro functional and preclinical pharmacokinetic assessment of molecules in this series are described.

Synthesis and antileukemic activity in vivo of the four diastereomeric 1-hydroxy-3,4-diaminocyclohexane-Cl2PtII complexes (Cl2PtII-3a-d) are described. Respective bis(phenylmethyl) (1 alpha,2 alpha,4 beta)-, (1 alpha,2 alpha,4 alpha)-, (1 alpha,2 beta,4 beta)-, and (1 alpha,2 beta,4 alpha)-(4-hydroxy-1,2-cyclohexanediyl)bis(carbamates) (5a, 5b, 7a, 7b) were prepared by hydroboration-oxidation of the bis(carbobenzoxyamino) derivatives (4,5) of cis- and trans-4,5-diaminocyclohexene. The relative stereochemistry of intermediates 5a and 5b was established by correlation with the alcohol obtained by NaBH4 reduction of bis(phenylmethyl) (1 alpha,2 alpha,3 alpha,4 alpha)-(3,4-epoxy-1,2-cyclohexanediyl)bis(carbamate) (8), the all-cis stereochemistry of which was unambiguously determined by X-ray crystallographic analysis. In the P-388 murine leukemia model these monohydroxycyclohexanediamine-PtII complexes were more effective than the PtII complexes of the related diol diamines 1a-e but were less active than the cisplatin positive control.

Stereochemical control during the epoxidation of cis -1-[N-Cbz]-2-[hydroxymethyl]-cyclohex-4-enes with MCPBA is dependent on hydroxyl functionalization which apparently determines ring conformation. Unprotected or acetate-derivatized compounds afford exclusively syn epoxide products. Silyl ether protected analogs furnish predominantly products derived from anti delivery of oxygen. Respective 2-carbomethoxy and benzyl carbamate-protected aminomethyl derivatives show stereospecificity similar to the free hydroxyl and acetate-protected substrates.

Stereocontrolled syntheses for the six diastereomeric 1,2-dihydroxy-4,5-diaminocyclohexanes 3a-f from cyclohexene diamines cis-4 and trans-5 are described. Cbz-protected species cis-9 and trans-11, respectively, served as a source of stable Cbz-protected precursors to these cyclohexanediol diamines (CDD), which were liberated upon catalytic (H2, Pd/C) hydrogenation. Catalytic osmylation of 9 afforded a mixture of diastereomeric diols 13 and 14, which served as precursors to cis-anti-cis CDD 3b and cis-syn-cis CDD 3a, respectively, whereas osmylation of 11 yielded the expected single product 12, the precursor to cis-anti-trans CDD 3d. Epoxidation of olefins 9 and 11 afforded oxiranes 15 and 17, respectively, which upon acid-catalyzed hydrolysis produced the corresponding Cbz-protected diols 16 and 18, which served as precursors to CDD trans-anti-cis 3c, and trans-anti-trans 3e. Formation of diol 18 from oxirane 17 was accompanied by formation of 2-oxa-4-azabicyclo[3.3.1]nonan-3-one 19. CDD trans-syn-trans 3f was prepared from diol 12 via regioselective monoacetylation, yielding 22, followed by oxidation to afford ketone 24. Sodium borohydride reduction and acetylation produced diacetate precursor 26. PtIICl2 complexes of five of the diamines (3a-d,f) are described, and their activities were compared with cisplatin (1) by employing P-388 leukemia implanted CDF1 mice. The data indicate that stereochemistry of the amino groups on the cyclohexanediamine ligand modulate the expression of toxic effects, and depending upon hydroxyl and amino group stereochemistry, there is a marked effect on complex formation (e.g., Cl2PtII-3e) and solubility characteristics (e.g., Cl2PtII-3c). Acetylation of the hydroxyl functions in selected isomers (28a-c) rendered the PtII complexes inactive. A single-crystal X-ray structure of compound 3a was determined at room temperature and indicated the cis-syn-cis arrangement of the OH and NH2 groups.