An inhibitor of RORγ for chronic pulmonary obstructive disease treatment.

The role of RORγ as a transcription factor for Th17 cell differentiation and thereby regulation of IL-17 levels is well known. Increased RORγ expression along with IL-17A levels was observed in animal models, immune cells and BAL fluid of COPD patients. Increased IL-17A levels in severe COPD patients are positively correlated with decreased lung functions and increased severity symptoms and emphysema, supporting an urgency to develop novel therapies modulating IL-17 or RORγ for COPD treatment. We identified a potent RORγ inhibitor, PCCR-1 using hit to lead identification followed by extensive lead optimization by structure-activity relationship. PCCR-1 resulted in RORγ inhibition with a high degree of specificity in a biochemical assay, with > 300-fold selectivity over other isoforms of ROR. Our data suggest promising potency for IL-17A inhibition in human and canine PBMCs and mouse splenocytes with no significant impact on Th1 and Th2 cytokines. In vivo, PCCR-1 exhibited significant efficacy in the acute CS model with dose-dependent inhibition of the PD biomarkers that correlated well with the drug concentration in lung and BAL fluid, demonstrating an acceptable safety profile. This inhibitor effectively inhibited IL-17A release in whole blood and BALf samples from COPD patients. Overall, we identified a selective inhibitor of RORγ to pursue further development of novel scaffolds for COPD treatment.

Oxidative DMSO Cyclization Cascade to Bicyclic Hydroxyketonitriles.

Thermolysis of ω-iodoalkyl-ß-siloxyalkenenitriles in DMSO triggers an oxidative cyclization cascade that affords highly oxygenated hydrindanones, decalones, and undecanones. The cyclization cascade is highly unusual on three counts: the cyclization installs a contiguous array of tertiary-quaternary-tertiary centers, thermolysis equilibrates a quaternary center, and the enolsilyl ether crossed-aldol proceeds without a catalyst.

Development of potent and selective Cathepsin C inhibitors free of aortic binding liability by application of a conformational restriction strategy.

Cathepsin C plays a key role in the activation of several degradative enzymes linked to tissue destruction in chronic inflammatory and autoimmune diseases. Therefore, Cathepsin C inhibitors could potentially be effective therapeutics for the treatment of diseases such as chronic obstructive pulmonary disease (COPD) or acute respiratory distress syndrome (ARDS). In our efforts towards the development of a novel series of Cathepsin C inhibitors, we started working around AZD5248 (1), an α-amino acid based scaffold having potential liability of aortic binding. A novel series of amidoacetonitrile based Cathepsin C inhibitors were developed by the application of a conformational restriction strategy on 1. In particular, this work led to the development of a potent and selective Cathepsin C inhibitor 3p, free of aortic binding liability.

Scaffold Morphing To Identify Novel DprE1 Inhibitors with Antimycobacterial Activity.

We report a novel benzimidazole (BI) based DprE1 inhibitor that resulted from scaffold morphing of a 1,4-azaindole series. The clinical progression of the 1,4-azaindole series from our previous work validates the potential of exploring newer chemical entities with antimycobacterial activity driven via a noncovalent inhibition of the decaprenylphosphoryl-ß-d-ribose-2'-epimerase (DprE1). The representative compounds from the new scaffold reported in this study exhibited an improved solubility and higher free plasma fraction, while retaining potent DprE1 inhibition and antimycobacterial activity. A representative compound from the benzimidazole series demonstrated good efficacy in a murine model of tuberculosis. Furthermore, molecular modeling of the BI scaffold suggests plausible modes of binding in the active site of DprE1 enzyme from Mycobacterium tuberculosis that can be used for further exploration of the series.

Triaminopyrimidine is a fast-killing and long-acting antimalarial clinical candidate.

The widespread emergence of Plasmodium falciparum (Pf) strains resistant to frontline agents has fuelled the search for fast-acting agents with novel mechanism of action. Here, we report the discovery and optimization of novel antimalarial compounds, the triaminopyrimidines (TAPs), which emerged from a phenotypic screen against the blood stages of Pf. The clinical candidate (compound 12) is efficacious in a mouse model of Pf malaria with an ED99 <30 mg kg(-1) and displays good in vivo safety margins in guinea pigs and rats. With a predicted half-life of 36 h in humans, a single dose of 260 mg might be sufficient to maintain therapeutic blood concentration for 4-5 days. Whole-genome sequencing of resistant mutants implicates the vacuolar ATP synthase as a genetic determinant of resistance to TAPs. Our studies highlight the potential of TAPs for single-dose treatment of Pf malaria in combination with other agents in clinical development.

Synthesis and in vitro evaluation of novel 8-aminoquinoline-pyrazolopyrimidine hybrids as potent antimalarial agents.

In the search of novel chemotherapeutic agents for emerging drug resistant parasites, the hybridization approaches have successfully emerged as an efficient tool in malarial chemotherapy. Herein, a rational design and synthesis of novel 8-aminoquinoline and pyrazolopyrimidine hybrids and their antimalarial activity against wild type Plasmodium falciparum (Pf_NF54) and resistant strain (Pf_K1) is reported. The medicinal chemistry approach to expand the scope of this series resulted in an identification of potent compounds with nanomolar potency (best IC50 5-10nM). Systematic structure activity relationship (SAR) studies revealed that pyrazolopyrimidine and 8-aminoquinoline ring are essential for achieving good P. falciparum potency. The docking study revealed that the compound 6 can retain some of the critical interactions within pfDHODH drug target.

Synthesis and biological evaluation of adamantane-based aminophenols as a novel class of antiplasmodial agents.

A series of adamantane based aminophenol derivatives were synthesized and evaluated for their antiplasmodial activity in vitro against Plasmodium falciparum (Pf_NF54) and resistant strain (Pf_K1). Herein, we report compounds resulting from this work that show excellent potency against both strains. Additionally, this series displayed excellent cytotoxicity selectivity index against THP1 cell line and had acceptable in vitro DMPK properties.

2-Phenylindole and Arylsulphonamide: Novel Scaffolds Bactericidal against Mycobacterium tuberculosis.

A cellular activity-based screen on Mycobacterium tuberculosis (Mtb) H37Rv using a focused library from the AstraZeneca corporate collection led to the identification of 2-phenylindoles and arylsulphonamides, novel antimycobacterial scaffolds. Both the series were bactericidal in vitro and in an intracellular macrophage infection model, active against drug sensitive and drug resistant Mtb clinical isolates, and specific to mycobacteria. The scaffolds showed promising structure-activity relationships; compounds with submicromolar cellular potency were identified during the hit to lead exploration. Furthermore, compounds from both scaffolds were tested for inhibition of known target enzymes or pathways of antimycobacterial drugs including InhA, RNA polymerase, DprE1, topoisomerases, protein synthesis, and oxidative-phosphorylation. Compounds did not inhibit any of the targets suggesting the potential of a possible novel mode of action(s). Hence, both scaffolds provide the opportunity to be developed further as leads and tool compounds to uncover novel mechanisms for tuberculosis drug discovery.

N-aryl-2-aminobenzimidazoles: novel, efficacious, antimalarial lead compounds.

From the phenotypic screening of the AstraZeneca corporate compound collection, N-aryl-2-aminobenzimidazoles have emerged as novel hits against the asexual blood stage of Plasmodium falciparum (Pf). Medicinal chemistry optimization of the potency against Pf and ADME properties resulted in the identification of 12 as a lead molecule. Compound 12 was efficacious in the P. berghei (Pb) model of malaria. This compound displayed an excellent pharmacokinetic profile with a long half-life (19 h) in rat blood. This profile led to an extended survival of animals for over 30 days following a dose of 50 mg/kg in the Pb malaria model. Compound 12 retains its potency against a panel of Pf isolates with known mechanisms of resistance. The fast killing observed in the in vitro parasite reduction ratio (PRR) assay coupled with the extended survival highlights the promise of this novel chemical class for the treatment of malaria.

Aminoazabenzimidazoles, a novel class of orally active antimalarial agents.

Whole-cell high-throughput screening of the AstraZeneca compound library against the asexual blood stage of Plasmodium falciparum (Pf) led to the identification of amino imidazoles, a robust starting point for initiating a hit-to-lead medicinal chemistry effort. Structure-activity relationship studies followed by pharmacokinetics optimization resulted in the identification of 23 as an attractive lead with good oral bioavailability. Compound 23 was found to be efficacious (ED90 of 28.6 mg·kg(-1)) in the humanized P. falciparum mouse model of malaria (Pf/SCID model). Representative compounds displayed a moderate to fast killing profile that is comparable to that of chloroquine. This series demonstrates no cross-resistance against a panel of Pf strains with mutations to known antimalarial drugs, thereby suggesting a novel mechanism of action for this chemical class.

1,4-azaindole, a potential drug candidate for treatment of tuberculosis.

New therapeutic strategies against multidrug-resistant (MDR) and extensively drug-resistant (XDR) Mycobacterium tuberculosis are urgently required to combat the global tuberculosis (TB) threat. Toward this end, we previously reported the identification of 1,4-azaindoles, a promising class of compounds with potent antitubercular activity through noncovalent inhibition of decaprenylphosphoryl-ß-D-ribose 2'-epimerase (DprE1). Further, this series was optimized to improve its physicochemical properties and pharmacokinetics in mice. Here, we describe the short-listing of a potential clinical candidate, compound 2, that has potent cellular activity, drug-like properties, efficacy in mouse and rat chronic TB infection models, and minimal in vitro safety risks. We also demonstrate that the compounds, including compound 2, have no antagonistic activity with other anti-TB drugs. Moreover, compound 2 shows synergy with PA824 and TMC207 in vitro, and the synergy effect is translated in vivo with TMC207. The series is predicted to have a low clearance in humans, and the predicted human dose for compound 2 is ≤1 g/day. Altogether, our data suggest that a 1,4-azaindole (compound 2) is a promising candidate for the development of a novel anti-TB drug.

Lead optimization of 1,4-azaindoles as antimycobacterial agents.

In a previous report, we described the discovery of 1,4-azaindoles, a chemical series with excellent in vitro and in vivo antimycobacterial potency through noncovalent inhibition of decaprenylphosphoryl-ß-d-ribose-2'-epimerase (DprE1). Nevertheless, high mouse metabolic turnover and phosphodiesterase 6 (PDE6) off-target activity limited its advancement. Herein, we report lead optimization of this series, culminating in potent, metabolically stable compounds that have a robust pharmacokinetic profile without any PDE6 liability. Furthermore, we demonstrate efficacy for 1,4-azaindoles in a rat chronic TB infection model. We believe that compounds from the 1,4-azaindole series are suitable for in vivo combination and safety studies.

4-aminoquinolone piperidine amides: noncovalent inhibitors of DprE1 with long residence time and potent antimycobacterial activity.

4-Aminoquinolone piperidine amides (AQs) were identified as a novel scaffold starting from a whole cell screen, with potent cidality on Mycobacterium tuberculosis (Mtb). Evaluation of the minimum inhibitory concentrations, followed by whole genome sequencing of mutants raised against AQs, identified decaprenylphosphoryl-ß-d-ribose 2'-epimerase (DprE1) as the primary target responsible for the antitubercular activity. Mass spectrometry and enzyme kinetic studies indicated that AQs are noncovalent, reversible inhibitors of DprE1 with slow on rates and long residence times of ∼100 min on the enzyme. In general, AQs have excellent leadlike properties and good in vitro secondary pharmacology profile. Although the scaffold started off as a single active compound with moderate potency from the whole cell screen, structure-activity relationship optimization of the scaffold led to compounds with potent DprE1 inhibition (IC50 < 10 nM) along with potent cellular activity (MIC = 60 nM) against Mtb.

Azaindoles: noncovalent DprE1 inhibitors from scaffold morphing efforts, kill Mycobacterium tuberculosis and are efficacious in vivo.

We report 1,4-azaindoles as a new inhibitor class that kills Mycobacterium tuberculosis in vitro and demonstrates efficacy in mouse tuberculosis models. The series emerged from scaffold morphing efforts and was demonstrated to noncovalently inhibit decaprenylphosphoryl-ß-D-ribose2'-epimerase (DprE1). With "drug-like" properties and no expectation of pre-existing resistance in the clinic, this chemical class has the potential to be developed as a therapy for drug-sensitive and drug-resistant tuberculosis.

Synthesis of privileged scaffolds by using diversity-oriented synthesis.

An elegant reagent-controlled strategy has been developed for the generation of a diverse range of biologically active scaffolds from a chiral bicyclic lactam. Reduction of the chiral lactam with LAH or alkylation with LHMDS to trigger different cyclization reactions have been shown to generate privileged scaffolds, such as pyrrolidines, indolines, and cyclotryptamines. Their amenability to substitution allows us to create various compound libraries by using these scaffolds. In silico studies were used to estimate the drug-like properties of these compounds. Selected compounds were subjected to anticancer screening by using three different cell lines. In addition, all these compounds were subjected to antibacterial screening to gauge the spectrum of biological activity that was conferred by our DOS methodology. Gratifyingly, with no additional iterative cycles, our method directly generated anticancer compounds with potency at low nanomolar concentrations, as represented by spiroindoline 14.

Reagent-based DOS: developing a diastereoselective methodology to access spirocyclic- and fused heterocyclic ring systems.

Herein, we report a diversity-oriented-synthesis (DOS) approach for the synthesis of biologically relevant molecular scaffolds. Our methodology enables the facile synthesis of fused N-heterocycles, spirooxoindolones, tetrahydroquinolines, and fused N-heterocycles. The two-step sequence starts with a chiral-bicyclic-lactam-directed enolate-addition/substitution step. This step is followed by a ring-closure onto the built-in scaffold electrophile, thereby leading to stereoselective carbocycle- and spirocycle-formation. We used in silico tools to calibrate our compounds with respect to chemical diversity and selected drug-like properties. We evaluated the biological significance of our scaffolds by screening them in two cancer cell-lines. In summary, our DOS methodology affords new, diverse scaffolds, thereby resulting in compounds that may have significance in medicinal chemistry.

Discovery of novel PI3-kinase δ specific inhibitors for the treatment of rheumatoid arthritis: taming CYP3A4 time-dependent inhibition.

PI3Kδ is a lipid kinase and a member of a larger family of enzymes, PI3K class IA(α, ß, δ) and IB (γ), which catalyze the phosphorylation of PIP2 to PIP3. PI3Kδ is mainly expressed in leukocytes, where it plays a critical, nonredundant role in B cell receptor mediated signaling and provides an attractive opportunity to treat diseases where B cell activity is essential, e.g., rheumatoid arthritis. We report the discovery of novel, potent, and selective PI3Kδ inhibitors and describe a structural hypothesis for isoform (α, ß, γ) selectivity gained from interactions in the affinity pocket. The critical component of our initial pharmacophore for isoform selectivity was strongly associated with CYP3A4 time-dependent inhibition (TDI). We describe a variety of strategies and methods for monitoring and attenuating TDI. Ultimately, a structure-based design approach was employed to identify a suitable structural replacement for further optimization.

Design, synthesis, and biological evaluation of new monoamine reuptake inhibitors with potential therapeutic utility in depression and pain.

Two new series of monoamine triple reuptake inhibitors (TRIs) have been discovered through scaffold homologation of our recently reported series of 3,3-disubstituted pyrrolidine TRIs. The regioisomeric 2- and 3-ketopyrrolidines demonstrated high levels of potency against all three monoamine transporters as well as good human in vitro stability, low drug-drug interaction potential and a decreased propensity for hERG channel binding. Representative compounds from these series displayed good in vivo pharmacokinetics and high monoamine receptor occupancies which are indicators of good brain penetration.

2-Substituted N-aryl piperazines as novel triple reuptake inhibitors for the treatment of depression.

Recently a class of compounds known as triple reuptake inhibitors has emerged as a new strategy for the treatment of depression. These compounds work by simultaneously inhibiting the synaptic reuptake of serotonin, norepinephrine and dopamine. In this Letter we describe the optimization of a novel series of 2-substituted N-aryl piperazine based triple reuptake inhibitors.

Novel, achiral aminoheterocycles as selective monoamine reuptake inhibitors.

A variety of novel aminoheterocycle scaffolds as selective monoamine reuptake inhibitors have been prepared and one of these scaffolds is achiral. The main elements responsible for hERG channel, CYP2D6 and CYP3A4 inhibition were identified.