Collaborative Virtual Screening Identifies a 2-Aryl-4-aminoquinazoline Series with Efficacy in an In Vivo Model of Trypanosoma cruzi Infection

Probing multiple proprietary pharmaceutical libraries in parallel via virtual screening allowed rapid expansion of the structure-activity relationship (SAR) around hit compounds with moderate efficacy against Trypanosoma cruzi, the causative agent of Chagas Disease. A potency-improving scaffold hop, followed by elaboration of the SAR via design guided by the output of the phenotypic virtual screening efforts, identified two promising hit compounds 54 and 85, which were profiled further in pharmacokinetic studies and in an in vivo model of T. cruzi infection. Compound 85 demonstrated clear reduction of parasitemia in the in vivo setting, confirming the interest in this series of 2-(pyridin-2-yl)quinazolines as potential anti-trypanosome treatments

Synthesis and properties of SMAPs 1-phospha-4-silabicyclo[2.2.2]octane derivatives

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).Part (vii): Special Issue Plenary and Invited Lectures ICHC-2

High-throughput screening of small-molecules libraries identified antibacterials against clinically relevant multidrug-resistant A. baumannii and K. pneumoniaeResearch in context

Summary: Background: The current pipeline for new antibiotics fails to fully address the significant threat posed by drug-resistant Gram-negative bacteria that have been identified by the World Health Organization (WHO) as a global health priority. New antibacterials acting through novel mechanisms of action are urgently needed. We aimed to identify new chemical entities (NCEs) with activity against Klebsiella pneumoniae and Acinetobacter baumannii that could be developed into a new treatment for drug-resistant infections. Methods: We developed a high-throughput phenotypic screen and selection cascade for generation of hit compounds active against multidrug-resistant (MDR) strains of K. pneumoniae and A. baumannii. We screened compound libraries selected from the proprietary collections of three pharmaceutical companies that had exited antibacterial drug discovery but continued to accumulate new compounds to their collection. Compounds from two out of three libraries were selected using “eNTRy rules” criteria associated with increased likelihood of intracellular accumulation in Escherichia coli. Findings: We identified 72 compounds with confirmed activity against K. pneumoniae and/or drug-resistant A. baumannii. Two new chemical series with activity against XDR A. baumannii were identified meeting our criteria of potency (EC50 ≤50 μM) and absence of cytotoxicity (HepG2 CC50 ≥100 μM and red blood cell lysis HC50 ≥100 μM). The activity of close analogues of the two chemical series was also determined against A. baumannii clinical isolates. Interpretation: This work provides proof of principle for the screening strategy developed to identify NCEs with antibacterial activity against multidrug-resistant critical priority pathogens such as K. pneumoniae and A. baumannii. The screening and hit selection cascade established here provide an excellent foundation for further screening of new compound libraries to identify high quality starting points for new antibacterial lead generation projects. Funding: BMBF and GARDP

Collaborative Virtual Screening Identifies a 2‑Aryl-4-aminoquinazoline Series with Efficacy in an In Vivo Model of Trypanosoma cruzi Infection

Probing multiple proprietary pharmaceutical libraries in parallel via virtual screening allowed rapid expansion of the structure–activity relationship (SAR) around hit compounds with moderate efficacy against Trypanosoma cruzi, the causative agent of Chagas Disease. A potency-improving scaffold hop, followed by elaboration of the SAR via design guided by the output of the phenotypic virtual screening efforts, identified two promising hit compounds 54 and 85, which were profiled further in pharmacokinetic studies and in an in vivo model of T. cruzi infection. Compound 85 demonstrated clear reduction of parasitemia in the in vivo setting, confirming the interest in this series of 2-(pyridin-2-yl)quinazolines as potential anti-trypanosome treatments

Repositioning and Characterization of 1-(Pyridin-4-yl)pyrrolidin-2-one Derivatives as Plasmodium Cytoplasmic Prolyl-tRNA Synthetase Inhibitors

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

Repositioning and Characterization of 1(Pyridin-4-yl)pyrrolidin-2-one Derivatives as Plasmodium Cytoplasmic Prolyl-tRNA Synthetase Inhibitors

[Image: see text] 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 × 10(5) parasites at a selection pressure of 3 × IC(50)) 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

Discovery of [<i>cis</i>-3-({(5<i>R</i>)‑5-[(7-Fluoro-1,1-dimethyl-2,3-dihydro‑1<i>H</i>‑inden-5-yl)carbamoyl]-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5<i>H</i>)‑yl}carbonyl)­cyclobutyl]­acetic Acid (TAK-828F) as a Potent, Selective, and Orally Available Novel Retinoic Acid Receptor-Related Orphan Receptor γt Inverse Agonist

A series of tetrahydro­naphthyridine derivatives as novel RORγt inverse agonists were designed and synthesized. We reduced the lipophilicity of tetrahydro­isoquinoline compound <b>1</b> by replacement of the trimethylsilyl group and SBDD-guided scaffold exchange, which successfully afforded compound <b>7</b> with a lower log <i>D</i> value and tolerable in vitro activity. Consideration of LLE values in the subsequent optimization of the carboxylate tether led to the discovery of [<i>cis</i>-3-({(5<i>R</i>)-5-[(7-fluoro-1,1-dimethyl-2,3-dihydro-1<i>H</i>-inden-5-yl)­carbamoyl]-2-methoxy-7,8-dihydro-1,6-naphthyridin-6­(5<i>H</i>)-yl}­carbonyl)­cyclobutyl]­acetic acid, TAK-828F (<b>10</b>), 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 <b>10</b> 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 <b>10</b> was selected as a clinical compound for the treatment of Th17-driven autoimmune diseases

Discovery of [<i>cis</i>-3-({(5<i>R</i>)‑5-[(7-Fluoro-1,1-dimethyl-2,3-dihydro‑1<i>H</i>‑inden-5-yl)carbamoyl]-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5<i>H</i>)‑yl}carbonyl)­cyclobutyl]­acetic Acid (TAK-828F) as a Potent, Selective, and Orally Available Novel Retinoic Acid Receptor-Related Orphan Receptor γt Inverse Agonist

A series of tetrahydro­naphthyridine derivatives as novel RORγt inverse agonists were designed and synthesized. We reduced the lipophilicity of tetrahydro­isoquinoline compound <b>1</b> by replacement of the trimethylsilyl group and SBDD-guided scaffold exchange, which successfully afforded compound <b>7</b> with a lower log <i>D</i> value and tolerable in vitro activity. Consideration of LLE values in the subsequent optimization of the carboxylate tether led to the discovery of [<i>cis</i>-3-({(5<i>R</i>)-5-[(7-fluoro-1,1-dimethyl-2,3-dihydro-1<i>H</i>-inden-5-yl)­carbamoyl]-2-methoxy-7,8-dihydro-1,6-naphthyridin-6­(5<i>H</i>)-yl}­carbonyl)­cyclobutyl]­acetic acid, TAK-828F (<b>10</b>), 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 <b>10</b> 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 <b>10</b> was selected as a clinical compound for the treatment of Th17-driven autoimmune diseases