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A phenotypic high-throughput screen allowed discovery of quinazolinone-2-carboxamide derivatives as a novel antimalarial scaffold. Structure-activity relationship studies led to identification of a potent inhibitor 19f, 95-fold more potent than the original hit compound, active against laboratory-resistant strains of malaria. Profiling of 19f suggested a fast in vitro killing profile. In vivo activity in a murine model of human malaria in a dose-dependent manner constitutes a concomitant benefit.

Delivering new medicines to patients suffering from Neglected Tropical Diseases (NTD) is a major challenge. There are various hurdles to be overcome, such as the large number of patients in a large number of different regions, the lack of marketability, and resistance to medicines. Takeda Pharmaceutical Company Limited (Takeda) is following a corporate mission of "striving towards better health for patients worldwide though leading innovation in medicine". These guiding principles lead to the values of Integrity, Fairness, Honesty and Perseverance that make up what we call "Takeda-ism". As part of its contribution to RD for NTDs, Takeda collaborates with global Product Development Partnerships (PDPs). In this symposium, the "Drug Discovery Booster" project to accelerate and expand discovery of new drugs for Leishmaniasis and Chagas disease with Drugs for Neglected Diseases initiative (DNDi) and other pharmaceutical companies is introduced. Proprietary compound libraries and the drug discovery expertise of various partners was applied to this new drug discovery approach. An overview of our research projects in malaria, tuberculosis, and NTD is also presented. In addition to these, Takeda's Access to Medicines (ATM) strategy and activities are introduced. Lastly, we discuss a new open innovation model which is accelerated by partnership with a variety of organizations and how Takeda achieves its sustainable development goal (SDG) targets.

Prolyl-tRNA synthetase (PRS) is a clinically validated antimalarial target. Screening of a set of PRS ATP-site binders, initially designed for human indications, led to identification of 1-(pyridin-4-yl)pyrrolidin-2-one derivatives representing a novel antimalarial scaffold. Evidence designates cytoplasmic PRS as the drug target. The frontrunner 1 and its active enantiomer 1- S exhibited low-double-digit nanomolar activity against resistant Plasmodium falciparum (Pf) laboratory strains and development of liver schizonts. No cross-resistance with strains resistant to other known antimalarials was noted. In addition, a similar level of growth inhibition was observed against clinical field isolates of Pf and P. vivax. The slow killing profile and the relative high propensity to develop resistance in vitro (minimum inoculum resistance of 8 × 105 parasites at a selection pressure of 3 × IC50) constitute unfavorable features for treatment of malaria. However, potent blood stage and antischizontal activity are compelling for causal prophylaxis which does not require fast onset of action. Achieving sufficient on-target selectivity appears to be particularly challenging and should be the primary focus during the next steps of optimization of this chemical series. Encouraging preliminary off-target profile and oral efficacy in a humanized murine model of Pf malaria allowed us to conclude that 1-(pyridin-4-yl)pyrrolidin-2-one derivatives represent a promising starting point for the identification of novel antimalarial prophylactic agents that selectively target Plasmodium PRS.

Prolyl-tRNA synthetase (PRS) is a clinically validated antimalarial target. Screening of a set of PRS ATP-site binders, initially designed for human indications, led to identification of 1-(pyridin-4-yl)pyrrolidin-2-one derivatives representing a novel antimalarial scaffold. Evidence designates cytoplasmic PRS as the drug target. The frontrunner 1 and its active enantiomer 1-S exhibited low-double-digit nanomolar activity against resistant Plasmodium falciparum (Pf) laboratory strains and development of liver schizonts. No cross-resistance with strains resistant to other known antimalarials was noted. In addition, a similar level of growth inhibition was observed against clinical field isolates of Pf and P. vivax. The slow killing profile and the relative high propensity to develop resistance in vitro (minimum inoculum resistance of 8 × 105 parasites at a selection pressure of 3 × IC50) constitute unfavorable features for treatment of malaria. However, potent blood stage and antischizontal activity are compelling for causal prophylaxis which does not require fast onset of action. Achieving sufficient on-target selectivity appears to be particularly challenging and should be the primary focus during the next steps of optimization of this chemical series. Encouraging preliminary off-target profile and oral efficacy in a humanized murine model of Pf malaria allowed us to conclude that 1-(pyridin-4-yl)pyrrolidin-2-one derivatives represent a promising starting point for the identification of novel antimalarial prophylactic agents that selectively target Plasmodium PRS.

A series of novel thiazole-containing amides were synthesized. A structure-activity relationship study of these compounds led to the identification of potent and selective PfFPPS/GGPPS inhibitors with good in vitro ADME profiles. The most promising candidate molecules were progressed to mouse in vivo PK studies and demonstrated adequate free drug exposure to warrant further investigation.

Novel small molecules were synthesized and evaluated as retinoic acid receptor-related orphan receptor-gamma t (RORγt) inverse agonists for the treatment of inflammatory and autoimmune diseases. A hit compound, 1, was discovered by high-throughput screening of our compound library. The structure-activity relationship (SAR) study of compound 1 showed that the introduction of a chlorine group at the 3-position of 4-cyanophenyl moiety increased the potency and a 3-methylpentane-1,5-diamide linker is favorable for the activity. The carbazole moiety of 1 was also optimized; a quinazolinedione derivative 18i suppressed the increase of IL-17A mRNA level in the lymph node of a rat model of experimental autoimmune encephalomyelitis (EAE) upon oral administration. These results indicate that the novel quinazolinedione derivatives have great potential as orally available small-molecule RORγt inverse agonists for the treatment of Th17-driven autoimmune diseases. A U-shaped bioactive conformation of this chemotype with RORγt protein was also observed.

A series of tetrahydroisoquinoline derivatives were designed, synthesized, and evaluated for their potential as novel orally efficacious retinoic acid receptor-related orphan receptor-gamma t (RORγt) inverse agonists for the treatment of Th17-driven autoimmune diseases. We carried out cyclization of the phenylglycinamide core by structure-based drug design and successfully identified a tetrahydroisoquinoline carboxylic acid derivative 14 with good biochemical binding and cellular reporter activity. Interestingly, the combination of a carboxylic acid tether and a central fused bicyclic ring was crucial for optimizing PK properties, and the compound 14 showed significantly improved PK profile. Successive optimization of the carboxylate tether led to the discovery of compound 15 with increased inverse agonistic activity and an excellent PK profile. Oral treatment of mice with compound 15 robustly and dose-dependently inhibited IL-17A production in an IL23-induced gene expression assay.

Retinoic-acid-related orphan receptor γt (RORγt) inverse agonists could be used for the treatment of autoimmune diseases. Previously, we reported a novel quinazolinedione 1 a with a flexible linear linker as a novel RORγt inverse agonist. A U-shaped conformation in the complex structure of 1 a with RORγt protein was confirmed. Further improvement of the pharmacokinetic (PK) profiles was required because of the low drug exposure in mice upon oral administration (mouse AUC of 1 a: 27 ng ⋅ h ⋅ mL-1 at 1 mg ⋅ kg-1 , p.o.). To improve the PK profiles, conformationally constrained U-shaped scaffolds were investigated. As a result, morpholine analogues with improved PK profiles and high potency were successfully identified. The substituent at the N1 position of the quinazoline moiety was also modified, leading to an enhancement of reporter activity. Consequently, compound 43 (N2 -(3-chloro-4-cyanophenyl)-N4 -(3-(cyclopropylmethyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-yl)morpholine-2,4-dicarboxamide) exhibited improved drug exposure (mouse AUC: 1289 ng ⋅ h ⋅ mL-1 at 1 mg ⋅ kg-1 , p.o.). In addition, suppression of IL-17A gene expression by IL-23 stimulation in a mouse pharmacodynamics model was observed for 43. The conformation of 43 with RORγt protein was also confirmed as U-shape by X-ray co-crystal structure analysis. The key interaction that boosts potency is also discussed.

Cryptosporidiosis is one of the leading causes of moderate to severe diarrhea in children in low-resource settings. The therapeutic options for cryptosporidiosis are limited to one drug, nitazoxanide, which unfortunately has poor activity in the most needy populations of malnourished children and HIV-infected persons. We describe here the discovery and early optimization of a class of imidazopyridine-containing compounds with potential for treating Cryptosporidium infections. The compounds target the Cryptosporidium methionyl-tRNA synthetase (MetRS), an enzyme that is essential for protein synthesis. The most potent compounds inhibited the enzyme with Ki values in the low picomolar range. Cryptosporidium cells in culture were potently inhibited with 50% effective concentrations as low as 7 nM and >1,000-fold selectivity over mammalian cells. A parasite persistence assay indicates that the compounds act by a parasiticidal mechanism. Several compounds were demonstrated to control infection in two murine models of cryptosporidiosis without evidence of toxicity. Pharmacological and physicochemical characteristics of compounds were investigated to determine properties that were associated with higher efficacy. The results indicate that MetRS inhibitors are excellent candidates for development for anticryptosporidiosis therapy.

A series of tetrahydronaphthyridine derivatives as novel RORγt inverse agonists were designed and synthesized. We reduced the lipophilicity of tetrahydroisoquinoline compound 1 by replacement of the trimethylsilyl group and SBDD-guided scaffold exchange, which successfully afforded compound 7 with a lower log D value and tolerable in vitro activity. Consideration of LLE values in the subsequent optimization of the carboxylate tether led to the discovery of [ cis-3-({(5 R)-5-[(7-fluoro-1,1-dimethyl-2,3-dihydro-1 H-inden-5-yl)carbamoyl]-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5 H)-yl}carbonyl)cyclobutyl]acetic acid, TAK-828F (10), which showed potent RORγt inverse agonistic activity, excellent selectivity against other ROR isoforms and nuclear receptors, and a good pharmacokinetic profile. In animal studies, oral administration of compound 10 exhibited robust and dose-dependent inhibition of IL-17A cytokine expression in a mouse IL23-induced gene expression assay. Furthermore, development of clinical symptoms in a mouse experimental autoimmune encephalomyelitis model was significantly reduced. Compound 10 was selected as a clinical compound for the treatment of Th17-driven autoimmune diseases.

Background/Aims: Retinoid-related orphan receptor gamma t (RORγt) is a master regulator of T helper 17 cells that plays a pivotal role in the production of inflammatory cytokines including interleukin (IL)-17. Therefore, RORγt has attracted much attention as a target receptor for the treatment of inflammatory diseases including rheumatoid arthritis, multiple sclerosis, inflammatory bowel diseases, and psoriasis. This study aims to characterize TAK-828F, a potent and selective RORγt inverse agonist. Methods: The biochemical properties of TAK-828F were evaluated using Time-Resolved Fluorescence Resonance Energy Transfer (TR-FRET) binding assay, surface plasmon resonance (SPR) biosensor assay, cofactor recruitment assay, reporter assay, and IL-17 expression assay. Results: TR-FRET binding assay and SPR biosensor assay revealed rapid, reversible, and high affinity binding of TAK-828F to RORγt. The cofactor recruitment assay showed that TAK-828F inhibited the recruitment of steroid receptor coactivator-1 to RORγt. Furthermore, TAK-828F inhibited the transcriptional activity of human and mouse RORγt with selectivity against human RORα and RORβ. TAK-828F also suppressed IL-17 production in Jurkat cells, overexpressing human RORγt. Conclusion: These favorable properties will be of advantage in the evaluation of TAK-828F in clinical studies for inflammatory diseases. Furthermore, these findings demonstrate that TAK-828F could serve as a pharmacological tool for further studies of RORγt and inflammatory diseases.

Retinoic acid-related orphan receptor γt (RORγt) is a key master regulator of the differentiation and activation of IL-17 producing CD4 + Th17, CD8 + Tc17 and IL-17/IFN-γ co-producing cells (Th1/17 cells). These cells play critical roles in the pathogenesis of autoimmune diseases such as inflammatory bowel disease and multiple sclerosis. Thus, RORγt is an attractive target for the treatment of these diseases. We discovered TAK-828F, an orally available potent and selective RORγt inverse agonist. The inhibitory effect on the activation and differentiation of Th17 cells by TAK-828F was evaluated in mouse and human primary cells. TAK-828F inhibited IL-17 production from mouse splenocytes and human peripheral blood mononuclear cells dose-dependently at concentrations of 0.01–10 μM without affecting the production of IFN-γ. Additionally, TAK-828F strongly inhibited Th17, Tc17 and Th1/17 cells’ differentiation from naive T cells and memory CD4 + T cells at 100 nM without affecting Th1 cells’ differentiation. In addition, TAK-828F improved Th17/Treg cells’ population ratio by inhibiting Th17 cells’ differentiation and up-regulating Treg cells. Furthermore, TAK-828F, at 100 nM, reduced the production of Th17-related cytokines (IL-17, IL-17F and IL-22) without affecting IFN-γ production in whole blood. These results demonstrate that TAK-828F has the potent and selective inhibitory activity against RORγt both in mouse and human cells. Additionally, oral administration of TAK-828F showed promising efficacy in naive T cell transfer mouse colitis model. TAK-828F may provide a novel therapeutic option to treat immune diseases by inhibiting Th17 and Th1/17 cells’ differentiation and improving imbalance between Th17 and Treg cells.

A series of novel phenylglycinamides as retinoic acid receptor-related orphan receptor-gamma t (RORγt) inverse agonists were discovered through optimization of a high-throughput screen hit 1. (R)-N-(2-((3,5-Difluoro-4-(trimethylsilyl)phenyl) amino)-1-(4-methoxyphenyl)-2-oxoethyl)-3-hydroxy-N-methylisoxazole-5-carboxamide (22) was identified as one of the best of these compounds. It displayed higher subtype selectivity and specificity over other nuclear receptors and demonstrated in vivo potency to suppress the transcriptional activity of RORγt in a mouse PD (pharmacodynamic) model upon oral administration.

A cationic gold(I) complex with a semihollow-shaped trialkynylphosphine catalyzed 5-exo-dig and 6-endo-dig cyclizations of various internal alkynic beta-keto esters, showing a marked advantage over a gold(I)-PPh3 complex with respect to the rates of the reactions and the product yields. It is proposed that the gold-bound alkynic substrate in a catalytic pocket must be somewhat folded and that such a steric effect makes the carbon-carbon bond formation entropically more favorable.

Part (vii): Special Issue Plenary and Invited Lectures ICHC-20, Synthesis and properties of a new class of trialkylphosphine ligands SMAPs (1-phospha-4-silabicyclo[2.2.2]octane derivatives, named after silicon-constrained monodentate alkylphosphine) with Me3P-like steric demand around the phosphorus center are described. A new feature of this class of ligands is the presence of a site for functionalization at the backside of the P-lone pair, which is not the case for Me3P. The SMAP ligands contain phosphorus and silicon atoms at each bridgehead of the bicyclo[2.2.2]octane framework. The molecular constraint of the bicyclic framework makes the steric demand around the phosphorus center as small as that of Me3P and projects the P-lone pair and the Si-substituent (R) in diametrically opposite directions on the straight line defined by the two bridgehead atoms. SMAP derivatives bearing Si substituents with varied electronic natures are obtainable by transforming the parent compound 4-phenyl-phospha-4-silabicyclo[2.2.2]octane (Ph-SMAP) through Si–Ph bond cleavage, and they constitute a class of electronically tunable trialkylphosphines. DFT calculations indicated that the parent ligand Ph-SMAP is similar to Me3P in donor power and that the tunable range of the donor power overlaps those of (t-Bu)3P and RAr2P (R: alkyl, Ar: aryl).

[reaction: see text] A new trialkylphosphine ligand with Me(3)P-like steric and electronic properties, 4-phenyl-1-phospha-4-silabicyclo[2.2.2]octane (Ph-SMAP), was synthesized. Given a phenyl group at the silicon atom, the Ph-SMAP ligand displayed nonvolatility with retention of Me(3)P-like properties. The new ligand was air-stable, crystalline, and easy to handle.

Solid-supported phosphine ligands silica−SMAPs {[silica gel 60N]−SMAP (1a) or [CARiACT Q-10]−SMAP (1b)}, which are composed of a caged, compact trialkylphosphine (SMAP) as a ligand and silica gel (...

A cationic gold(I) complex with a semihollow-shaped trialkynylphosphine catalyzed 5-exo-dig and 6-endo-dig cyclizations of various internal alkynic β-keto esters, showing a marked advantage over a gold(I)−PPh3 complex with respect to the rates of the reactions and the product yields. It is proposed that the gold-bound alkynic substrate in a catalytic pocket must be somewhat folded and that such a steric effect makes the carbon−carbon bond formation entropically more favorable.

Synthesis, properties, and catalytic applications of a caged trialkylphosphine ligand with Me3P-like steric and electronic characters, 4-phenyl-1-phospha-4-silabicyclo[2.2.2]octane (Ph-SMAP), are reported. Given a phenyl group at the silicon atom, the Ph-SMAP ligand displayed nonvolatility with retention of Me3P-like steric and electronic properties. The new ligand is air-stable, crystalline, and easy to handle. Single-crystal X-ray diffraction analyses of Ph-SMAP and its coordination compounds such as borane, rhodium(I), and Pt(II) complexes revealed a rigid, linear structural feature of the Ph-SMAP framework. DFT calculations [B3LYP/6-31G(d,p)] indicated that the electron-donating ability of Ph-SMAP is slightly stronger than that of Me3P and that replacement of Si atom of Ph-SMAP with a carbon atom drastically decreases the donor power. The Ph-SMAP ligand markedly accelerated the rhodium-catalyzed hydrosilylation and hydrogenation of ketones as compared with the effect of conventional phosphine ligands ...

Trialkynylphosphines substituted with bulky triarylsilyl groups at the alkyne termini were synthesized. The new phosphines P(C[triple chemical bond]CSiAr(3))(3) (Ar=3,5-tBu(2)-4-MeOC(6)H(2), 3,5-(Me(3)Si)(2)C(6)H(3)) are uncrowded near the phosphorus atom but bulky in the distal region. As a result, they contain a large cavity, at the bottom of which the phosphine lone-pair electrons are located. The compounds are stable to oxidation by air and hydrolysis. DFT calculations suggested that the triethynylphosphines are good pi-acceptor ligands, comparable with P(OAr)(3). The trialkynylphosphines reacted with [{RhCl(cod)}(2)] (P/Rh=1.1:1) to give selectively the monophosphine-rhodium complex [RhCl(cod)P(C[triple chemical bond]CSiAr(3))(3)]. X-ray crystal-structure analysis revealed that the {RhCl(cod)} fragment is fully accommodated by the cavity of the phosphine ligand. Compared to the effect of analogues with smaller end caps and PPh(3), the trialkynylphosphines accelerated markedly the rhodium-catalyzed hydrosilylation of ketones with a triorganosilane. It is proposed that the higher catalytic activity observed with the holey phosphines is a result of the preferential formation of a monophosphine-rhodium species.

A series of silicon-constrained monodentate trialkylphosphines SMAPs bearing a Si substituent with diverse electronic natures were synthesized. DFT calculations and NMR measurements indicated that ...

The synthesis, properties and catalytic uses of phosphinoalkynes bearing bulky end caps at the alkyne termini, that is, tris[(triarylsilyl)ethynyl]phosphines are reported. The most salient feature of the new phosphines is the holey molecular shape possessing a deep and large-scale metal-binding cavity. The holey phosphines displayed remarkable rate enhancement in the gold(I)-catalyzed six- and seven-membered ring forming cyclizations of acetylenic keto esters and 1,7-enynes. It is proposed that the cavity in the ligand forces a nucleophilic center (enol or alkene) of the acetylenic compounds close to the gold-bound alkyne, making ring-closing anti attack feasible.