Impact of Cross-Coupling Reactions in Drug Discovery and Development.

Cross-coupling reactions have played a critical role enabling the rapid expansion of structure-activity relationships (SAR) during the drug discovery phase to identify a clinical candidate and facilitate subsequent drug development processes. The reliability and flexibility of this methodology have attracted great interest in the pharmaceutical industry, becoming one of the most used approaches from Lead Generation to Lead Optimization. In this mini-review, we present an overview of cross-coupling reaction applications to medicinal chemistry efforts, in particular the Suzuki-Miyaura and Buchwald-Hartwig cross-coupling reactions as a remarkable resource for the generation of carbon-carbon and carbon-heteroatom bonds. To further appreciate the impact of this methodology, the authors discuss some recent examples of clinical candidates that utilize key cross-coupling reactions in their large-scale synthetic process. Looking into future opportunities, the authors highlight the versatility of the cross-coupling reactions towards new chemical modalities like DNA-encoded libraries (DELs), new generation of peptides and cyclopeptides, allosteric modulators, and proteolysis targeting chimera (PROTAC) approaches.

Breakthroughs in neuroactive steroid drug discovery.

Endogenous and synthetic neuroactive steroids (NASs) or neurosteroids are effective modulators of multiple signaling pathways including receptors for the γ-aminobutyric acid A (GABAA) and glutamate, in particular N-methyl-d-aspartate (NMDA). These receptors are the major inhibitory and excitatory neurotransmitters in the central nervous system (CNS), and there is growing evidence suggesting that dysregulation of neurosteroid production plays a role in numerous neurological disorders. The significant unmet medical need for treatment of CNS disorders has increased the interest for these types of compounds. In this review, we highlight recent progress in the clinical development of NAS drug candidates, in addition to preclinical breakthroughs in the identification of novel NASs, mainly for GABAA and NMDA receptor modulation.

Discovery of dual positive allosteric modulators (PAMs) of the metabotropic glutamate 2 receptor and CysLT1 antagonists for treating migraine headache.

Pyridylmethylsulfonamide series were the first reported example of positive allosteric modulators (PAM) of the mGlu2 receptor. The hydroxyacetophenone scaffold is a second series of mGlu2 PAMs we have identified. This series of molecules are potent mGlu2 potentiators and possess significant CysLT1 (cysteinyl leukotriene receptor 1) antagonist activity, showing in vivo efficacy in a dural plasma protein extravasation (PPE) model of migraine. In this paper, we describe the dual SAR, pharmacokinetics and preclinical in vivo efficacy data for a tetrazole containing hydroxyacetophenone scaffold.

Discovery of substituted-2,4-dimethyl-(naphthalene-4-carbonyl)amino-benzoic acid as potent and selective EP4 antagonists.

A novel series of EP4 antagonists, based on a quinoline scaffold, has been discovered. Medicinal chemistry efforts to optimize the potency of the initial hit are described. A highly potent compound in a clinically relevant human whole blood assay was identified. Selectivity and pharmacokinetic profiles of this compound are discussed.

Identification and biological activity of 6-alkyl-substituted 3-methyl-pyridine-2-carbonyl amino dimethyl-benzoic acid EP4 antagonists.

Continued SAR optimization of a series of 3-methylpyridine-2-carbonyl amino-2,4-dimethyl-benzoic acid led to the selection of compound 4f for clinical studies. Compound 4f showed an IC50 of 123nM for inhibition of PGE2-induced TNFα reduction in an ex vivo LPS-stimulated human whole blood assay (showing >10-fold increase over clinical compound CJ-023,423). Pharmacokinetic profile, selectivity and in vivo efficacy comparing 4f to NSAID diclofenac in the monoiodoacetic acid (MIA) pain model and adjuvant induced arthritis (AIA) inflammatory model are included.

Discovery of potent aryl-substituted 3-[(3-methylpyridine-2-carbonyl) amino]-2,4-dimethyl-benzoic acid EP4 antagonists with improved pharmacokinetic profile.

Two new series of EP4 antagonists containing a 3-methylaryl-2-carbonyl core have been identified. One series has a 3-substituted-phenyl core, while the other one incorporates a 3-substituted pyridine. Both series led to compounds with potent activity in functional and human whole blood (hWB) assays. In the pyridine series, compound 7a was found to be a highly potent and selective EP4 antagonist, with suitable rat and dog pharmacokinetic profiles.

Novel bicyclo[3.1.0]hexane analogs as antagonists of metabotropic glutamate 2/3 receptors for the treatment of depression.

Negative modulators of metabotropic glutamate 2 & 3 receptors demonstrate antidepressant-like activity in animal models and hold promise as novel therapeutic agents for the treatment of major depressive disorder. Herein we describe our efforts to prepare and optimize a series of conformationally constrained 3,4-disubstituted bicyclo[3.1.0]hexane glutamic acid analogs as orthosteric (glutamate site) mGlu2/3 receptor antagonists. This work led to the discovery of a highly potent and efficacious tool compound 18 (hmGlu2 IC50 46±14.2nM, hmGlu3 IC50=46.1±36.2nM). Compound 18 showed activity in the mouse forced swim test with a minimal effective dose (MED) of 1mg/kg ip. While in rat EEG studies it exhibited wake promoting effects at 3 and 10mg/kg ip without any significant effects on locomotor activity. Compound 18 thus represents a novel tool molecule for studying the impact of blocking mGlu2/3 receptors both in vitro and in vivo.

Physiological and biochemical mechanisms of the ornamental Eugenia myrtifolia L. plants for coping with NaCl stress and recovery.

MAIN CONCLUSION: We studied the response of Eugenia myrtifolia L. plants, an ornamental shrub native to tropical and subtropical areas, to salt stress in order to facilitate the use of these plants in Mediterranean areas for landscaping. E. myrtifolia plants implement a series of adaptations to acclimate to salinity, including morphological, physiological and biochemical changes. Furthermore, the post-recovery period seems to be detected by Eugenia plants as a new stress situation. Different physiological and biochemical changes in Eugenia myrtifolia L. plants after being subjected to NaCl stress for up to 30 days (Phase I) and after recovery from salinity (Phase II) were studied. Eugenia plants proved to be tolerant to NaCl concentrations between 44 and 88 mM, displaying a series of adaptative mechanisms to cope with salt-stress, including the accumulation of toxic ions in roots. Plants increased their root/shoot ratio and decreased their leaf area, leaf water potential and stomatal conductance in order to limit water loss. In addition, they displayed different strategies to protect the photosynthetic machinery, including the limited accumulation of toxic ions in leaves, increase in chlorophyll content, changes in chlorophyll fluorescence parameters, leaf anatomy and antioxidant defence mechanisms. Anatomical modifications in leaves, including an increase in palisade parenchyma and intercellular spaces and decrease in spongy parenchyma, served to facilitate CO2 diffusion in a situation of reduced stomatal aperture. Salinity produced oxidative stress in Eugenia plants as evidenced by oxidative stress parameters values and a reduction in APX and ASC levels. Nevertheless, SOD and GSH contents increased. The post-recovery period is detected as a new stress situation, as observed through effects on plant growth and alterations in chlorophyll fluorescence and oxidative stress parameters.

Target engagement in lead generation.

The pharmaceutical industry is currently facing multiple challenges, in particular the low number of new drug approvals in spite of the high level of R&D investment. In order to improve target selection and assess properly the clinical hypothesis, it is important to start building an integrated drug discovery approach during Lead Generation. This should include special emphasis on evaluating target engagement in the target tissue and linking preclinical to clinical readouts. In this review, we would like to illustrate several strategies and technologies for assessing target engagement and the value of its application to medicinal chemistry efforts.

Discovery of selective N-[3-(1-methyl-piperidine-4-carbonyl)-phenyl]-benzamide-based 5-HT1 F receptor agonists: Evolution from bicyclic to monocyclic cores.

Preclinical experiments and clinical observations suggest the potential effectiveness of selective 5-HT1F receptor agonists in migraine. Identifying compounds with enhanced selectivity is crucial to assess its therapeutic value. Replacement of the indole nucleus in 2 (LY334370) with a monocyclic phenyl ketone moiety generated potent and more selective 5-HT1F receptor agonists. Focused SAR studies around this central phenyl ring demonstrated that the electrostatic and steric interactions of the substituent with both the amide CONH group and the ketone CO group play pivotal roles in affecting the adopted conformation and thus the 5-HT1F receptor selectivity. Computational studies confirmed the observed results and provide a useful tool in the understanding of the conformational requirements for 5-HT1F receptor agonist activity and selectivity. Through this effort, the 2-F-phenyl and N-2-pyridyl series were also identified as potent and selective 5-HT1F receptor agonists.

Protective effects of Glomus iranicum var. tenuihypharum on soil and Viburnum tinus plants irrigated with treated wastewater under field conditions.

Currently, irrigation using recycled water is increasing, especially in semiarid environments, but a potential problem of using reclaimed wastewater is its elevated salt levels. The application of arbuscular mycorrhizal fungi (AMF) could be a suitable option to mitigate the negative effects produced by the salinity. In this work, the combined effect of Glomus iranicum var. tenuihypharum and two types of water: Control, C, with EC <0.9 dS m(-1) and reclaimed water (wastewater previously treated in a sewage treatment plant) with EC 4 dS m(-1) during a first saline period (11 weeks) and with EC 6 dS m(-1) during a second saline period (25 weeks), was evaluated for laurustinus (Viburnum tinus) plants under field conditions. This plant is a popular shrub very used for gardening. Chemical properties of soil as well as physiological behavior, leaf nutrition, and esthetic value of plants were evaluated. Due to the high salinity from wastewater at 6 dS m(-1), laurustinus plants decreased their stem water potential values and, to a lesser extent, the stomatal conductance. Also, the visual quality of the plants was diminished. The inoculated AMF satisfactorily colonized the laurustinus roots and enhanced the structure of the soil by increasing the glomalin and carbon contents. Furthermore, G. iranicum var. tenuihypharum inoculation decreased Na and Cl content, stimulated flowering and improved the stem water potential of the plants irrigated with both types of reclaimed water. The AMF also had a positive effect as a consequence of stimulation of plant physiological parameters, such as the stem water potential and stomatal conductance. Effective AMF associations that avoid excessive salinity could provide wastewater reuse options, especially when the plants grow in soils.

Empowering Voices: Inspiring Women in Medicinal Chemistry.

As we celebrate International Women's Day 2024 with the theme "Inspire Inclusion", the women of the ACS Medicinal Chemistry Division (MEDI) want to foster a sense of belonging, relevance, and empowerment by sharing uplifting stories of what inspired them to become medicinal chemists. In this editorial, we are featuring female medicinal chemistry scientists to provide role models, encouragement, and inspiration to others. We asked women medicinal chemists to contribute a brief paragraph about what inspired them to become medicinal chemists or what inspires them today as medicinal chemists. The responses and contributions highlight their passions and motivations, such as their love of the sciences and their drive to improve human health by contributing to basic research and creating lifesaving drugs.

Empowering Voices: Inspiring Women in Medicinal Chemistry.

As we celebrate International Women's Day 2024 with the theme "Inspire Inclusion", the women of the ACS Medicinal Chemistry Division (MEDI) want to foster a sense of belonging, relevance, and empowerment by sharing uplifting stories of what inspired them to become medicinal chemists. In this editorial, we are featuring female medicinal chemistry scientists to provide role models, encouragement, and inspiration to others. We asked women medicinal chemists to contribute a brief paragraph about what inspired them to become medicinal chemists or what inspires them today as medicinal chemists. The responses and contributions highlight their passions and motivations, such as their love of the sciences and their drive to improve human health by contributing to basic research and creating lifesaving drugs.

Water relations, nutrient content and developmental responses of Euonymus plants irrigated with water of different degrees of salinity and quality.

For 20 weeks, the physiological responses of Euonymus japonica plants to different irrigation sources were studied. Four irrigation treatments were applied at 100 % water holding capacity: control (electrical conductivity (EC) <0.9 dS m(-1)); irrigation water normally used in the area (irrigator's water) IW (EC: 1.7 dS m(-1)); NaCl solution, NaCl (EC: 4 dS m(-1)); and wastewater, WW (EC: 4 dS m(-1)). This was followed by a recovery period of 13 weeks, when all the plants were rewatered with the same amount and quality of irrigation water as the control plants. Despite the differences in the chemical properties of the water used, the plants irrigated with NaCl and WW showed similar alterations in growth and size compared with the control even at the end of the recovery period. Leaf number was affected even when the EC of the irrigation water was of 1.7 dS m(-1) (IW), indicating the salt sensitivity of this parameter. Stomatal conductance (gs) and photosynthesis (Pn), as well as stem water potential (Ψstem), were most affected in plants irrigated with the most saline waters (NaCl and WW). At the end of the experiment the above parameters recovered, while IW plants showed similar values to the control. The higher Na(+) and Cl(+) uptake by NaCl and WW plants led them to show osmotic adjustment throughout the experiment. The highest amount of boron found in WW plants did not affect root growth. Wastewater can be used as a water management strategy for ornamental plant production, as long as the water quality is not too saline, since the negative effect of salt on the aesthetic value of plants need to be taken into consideration.

Accelerating Drug Discovery: Synthesis of Complex Chemotypes via Multicomponent Reactions.

The generation of multiple bonds in one reaction step has attracted massive interest in drug discovery and development. Multicomponent reactions (MCRs) offer the advantage of combining three or more reagents in a one-pot fashion to effectively yield a synthetic product. This approach significantly accelerates the synthesis of relevant compounds for biological testing. However, there is a perception that this methodology will only produce simple chemical scaffolds with limited use in medicinal chemistry. In this Microperspective, we want to highlight the value of MCRs toward the synthesis of complex molecules characterized by the presence of quaternary and chiral centers. This paper will cover specific examples showing the impact of this technology toward the discovery of clinical compounds and recent breakthroughs to expand the scope of the reactions toward topologically rich molecular chemotypes.

Excellence in Medicinal Chemistry: Celebrating ACS Medicinal Chemistry Division (MEDI) Awards. A Call for Nominations.

The American Chemical Society Division of Medicinal Chemistry (MEDI) confers a range of awards, fellowships and honors to recognize excellence in medicinal chemistry. To celebrate the creation of the Gertrude Elion Medical Chemistry Award the ACS MEDI Division wishes to take this opportunity to inform the community of the many awards, fellowships and travel grants that are available for members.

Morphological performance and seasonal pattern of water relations and gas exchange in Pistacia lentiscus plants subjected to salinity and water deficit.

Soil water deficit and salinity represent a major factor impacting plant survival and agricultural production. The frequency and severity of both abiotic stresses are expected to increase in a context of climate change, especially in arid and semi-arid regions. This work studied the growth pattern, biomass and mineral distribution and the seasonal pattern of water status, photosynthetic rate and stomatal conductance in plant of Pistacia lentiscus grown under different levels of water deficit and salinity. P. lentiscus plants growing under greenhouse conditions were subjected to four irrigation treatments during 11 months: control (C, 1 dS m-1), moderate water deficit (MW, 1dS m-1, 60% of the control), severe water deficit (SW, 1 dS m-1, 40% of the control) and saline (S, 4dS m-1). The results show that Pistacia lentiscus plants were more affected by deficit irrigation than salinity. Deficit irrigation and salinity inhibited plant height, with reductions of 20%, 22% and 35% for S, MW and SW, respectively. Total leaf area was not modified by effect of the treatments, with the result that plant compactness increased in MW. The salt stressed plants only showed lower relative growth rate at the end of the experiment. Plants responded to saline or drought stress by increasing their osmotic adjustment, which was more pronounced under salinity. Saline plants had the highest values in Na+ and Cl- ions and the lowest values for K+/Na+ and Ca2+/Na+ ratios in leaves and stems, which is correlated with a decrease in growth, stomatal conductance, photosynthesis and stem water potential, and can be used as a diagnostic tool to assess plant tolerance to salinity stress. As a measure of plant hydration, relative water content was more sensitive to deficit irrigation than salinity, being a good indicator of water stress. P. lentiscus plants subjected to both deficit irrigation treatments exhibited an increase in their intrinsic water use efficiency, which is an important adaptation for plants growing in environments with water scarcity.

Enhancing the Visibility of Women in the ACS Division of Medicinal Chemistry (ACS MEDI).

On the occasion of the 2023 International Women's Day on March 8, 2023, we want to celebrate and highlight the contributions of many women volunteers in the American Chemical Society Division of Medicinal Chemistry (ACS MEDI).

Enhancing the Visibility of Women in the ACS Division of Medicinal Chemistry (ACS MEDI).

On the occasion of the 2023 International Women's Day on March 8, 2023, we want to celebrate and highlight the contributions of many women volunteers in the American Chemical Society Division of Medicinal Chemistry (ACS MEDI).

How hydrogen bonds impact P-glycoprotein transport and permeability.

The requirement to cross a biological membrane can be a complex process especially if multidrug transporters such as P-gp must be considered. Drug partitioning into the lipid membrane and efflux by P-gp are tightly coupled processes wherein H-bonding interactions play a key role. All H-bond donors and acceptors are not equal in terms of the strength of the H-bonds that they form, hence it is important to consider their relative strength. Using various examples from literature, we illustrate the benefits of considering the relative strengths of individual H-bonds and introducing intramolecular H-bonds to increase membrane permeability and/or decrease P-gp efflux.