Explore the vast range of titles available.

Daily use of atogepant (a small-molecule, calcitonin gene–related peptide receptor antagonist) at any of three doses resulted in greater reductions in migraine days per month over a period of 12 weeks than did placebo. Nausea and constipation were side effects in approximately 5% of the participants who received atogepant.

Introduction and Objective Pulmonary capillary endothelial transient receptor potential vanilloid 4 (TRPV4) channel plays a critical role in mediating the development of cardiogenic pulmonary edema. GSK2798745 is a first-in-class, highly potent, selective, orally active TRPV4 channel blocker being evaluated in a first-time-in-humans study (NCT02119260). Methods GSK2798745 was administered in a randomized, placebo-controlled study design to healthy volunteers in three separate cohorts as single escalating doses, with and without food, and as once-daily repeat doses for up to 14 days, respectively. Two cohorts of subjects with mild to moderate heart failure were also administered GSK2798745 once daily for up to 7 days. Safety, tolerability, and systemic exposure data were collected. Results No significant safety issues or serious adverse events were observed with GSK2798745 in healthy volunteers and patients with heart failure. GSK2798745 systemic exposure data demonstrated linear pharmacokinetics up to 12.5 mg, less than twofold accumulation with once-daily dosing, and a systemic half-life of ~ 13 h. There was a slight increase in GSK2798745 exposure [14% increase in area under the plasma concentration–time curve (AUC) and 9% increase in maximum observed plasma concentration ( C max )] after administration with a high-fat meal. Conclusions GSK2798745 was well-tolerated in healthy volunteers and patients with stable heart failure. The safety and exposure data obtained in this study allow further evaluation of the drug in long-term clinical studies in heart failure as well as other indications.

The core symptoms of autism spectrum disorder (ASD) include impaired social communication, repetitive behaviors, and restricted interests. No effective pharmacotherapy for these core deficits exists. Within the domain of social communication, the vasopressin system is implicated in social cognition and social signaling deficits of ASD, and represents a potential therapeutic target. We assessed the effects of a single 20 mg intravenous dose of the arginine vasopressin receptor 1A (V1a) antagonist, RG7713, on exploratory biomarkers (eye tracking), behavioral and clinical measures of social cognition and communication (affective speech recognition (ASR), reading the mind in the eyes, olfactory identification, scripted interaction), and safety and tolerability in a multicenter, randomized, double-blind, placebo-controlled, cross-over study of 19 high-functioning adult male subjects with DSM-IV Autistic Disorder (age 18-45 years; full scale IQ >70; ABC-Irritability subscale ⩽13). Eye-tracking showed an increase in biological motion orienting preference with RG7713 (ES=0.8, p=0.047) and a non-significant improvement in the composite score (ES=0.2, p=0.29). RG7713 reduced ability to detect lust (ES=-0.8, p=0.03) and fear (ES=-0.7, p=0.07) in ASR. However, when all eight individual emotion subscales were combined into an overall ASR performance score, the reduction was non-significant (ES=-0.1, p=0.59). Thirteen adverse events were reported in 10 subjects; all were of mild (11/13) or moderate (2/13) severity. Although interpretation should be cautious due to multiple comparisons and small sample size, these results provide preliminary evidence from experimental and behavioral biomarkers, that blockade of the V1a receptor may improve social communication in adults with high-functioning ASD. ClinicalTrials.gov identifier: NCT01474278 A Study of RO5028442 in Adult Male High-Functioning Autistic Patients. Available at: https://clinicaltrials.gov/ct2/show/NCT01474278.

Administration of artemisinin-based combination therapy (ACT) to infant and young children can be challenging. A formulation with accurate dose and ease of administration will improve adherence and compliance in children. The fixed-dose combination dispersible tablet of arterolane maleate (AM) 37.5 mg and piperaquine phosphate (PQP) 187.5 mg can make dosing convenient in children. This multicenter (India and Africa), comparative, parallel-group trial enrolled 859 patients aged 6 months to 12 years with Plasmodium falciparum malaria. Patients were randomized in a ratio of 2:1 to AM-PQP (571 patients) once daily and artemether-lumefantrine (AL) (288 patients) twice daily for 3 days and followed for 42 days. The cure rate (ie, polymerase chain reaction-corrected adequate clinical and parasitological response) in the per-protocol population at day 28 was 100.0% and 98.5% (difference, 1.48% [95% confidence interval {CI}, .04%-2.91%]) in the AM-PQP and AL arms, respectively, and 96.0% and 95.8% (difference, 0.14% [95% CI, -2.68% to 2.95%]) in the intention-to-treat (ITT) population. The cure rate was comparable at day 42 in the ITT population (AM-PQP, 94.4% vs AL, 93.1%). The median parasite clearance time was 24 hours in both the arms. The median fever clearance time was 6 hours in AM-PQP and 12 hours in the AL arm. Both the treatments were found to be safe and well tolerated. Overall, safety profile of both the treatments was similar. The efficacy and safety of fixed-dose combination of AM and PQP was comparable to AL for the treatment of uncomplicated P. falciparum malaria in pediatric patients. CTRI/2014/07/004764.

Increases in antimicrobial resistance are creating challenges for the treatment of gonorrhea. Zoliflodacin is a new antimicrobial agent that inhibits DNA biosynthesis. In this phase 2 trial, zoliflodacin is shown to have activity against uncomplicated urogenital gonorrhea.

Recent reports of increased tolerance to artemisinin derivatives--the most recently adopted class of antimalarials--have prompted a need for new treatments. The spirotetrahydro-β-carbolines, or spiroindolones, are potent drugs that kill the blood stages of Plasmodium falciparum and Plasmodium vivax clinical isolates at low nanomolar concentration. Spiroindolones rapidly inhibit protein synthesis in P. falciparum, an effect that is ablated in parasites bearing nonsynonymous mutations in the gene encoding the P-type cation-transporter ATPase4 (PfATP4). The optimized spiroindolone NITD609 shows pharmacokinetic properties compatible with once-daily oral dosing and has single-dose efficacy in a rodent malaria model.

In tumours that harbour wild-type p53, p53 protein function is frequently disabled by the mouse double minute 2 protein (MDM2, or HDM2 in humans). Multiple HDM2 antagonists are currently in clinical development. Preclinical data indicate that TP53 mutations are a possible mechanism of acquired resistance to HDM2 inhibition; however, this resistance mechanism has not been reported in patients. Utilizing liquid biopsies, here we demonstrate that TP53 mutations appear in circulating cell-free DNA obtained from patients with de-differentiated liposarcoma being treated with an inhibitor of the HDM2–p53 interaction (SAR405838). TP53 mutation burden increases over time and correlates with change in tumour size, likely representing selection of TP53 mutant clones resistant to HDM2 inhibition. These results provide the first clinical demonstration of the emergence of TP53 mutations in response to an HDM2 antagonist and have significant implications for the clinical development of this class of molecules. Pre-clinical studies have shown that TP53 mutations can account for acquired resistance to HDM2 antagonists. This study provides clinical evidence for the emergence of TP53 mutations in circulating cell-free DNA, seen in 5 out of 20 de-differentiated liposarcoma patients treated with an HDM2 antagonist.

The benzothiazinone lead compound, BTZ043, kills Mycobacterium tuberculosis by inhibiting the essential flavo‐enzyme DprE1, decaprenylphosphoryl‐beta‐D‐ribose 2‐epimerase. Here, we synthesized a new series of piperazine‐containing benzothiazinones (PBTZ) and show that, like BTZ043, the preclinical candidate PBTZ169 binds covalently to DprE1. The crystal structure of the DprE1‐PBTZ169 complex reveals formation of a semimercaptal adduct with Cys387 in the active site and explains the irreversible inactivation of the enzyme. Compared to BTZ043, PBTZ169 has improved potency, safety and efficacy in zebrafish and mouse models of tuberculosis (TB). When combined with other TB drugs, PBTZ169 showed additive activity against M. tuberculosis in vitro except with bedaquiline (BDQ) where synergy was observed. A new regimen comprising PBTZ169, BDQ and pyrazinamide was found to be more efficacious than the standard three drug treatment in a murine model of chronic disease. PBTZ169 is thus an attractive drug candidate to treat TB in humans. Synopsis Tuberculosis (TB) drug resistance is still spreading worldwide, emphasizing the need for new efficient drug combinations. PBTZ169 is here presented as an optimized, potent and synergistic preclinical drug candidate for the treatment of TB in humans. The development of a new candidate drug, PBTZ169, for the treatment of tuberculosis is described. Atomic level understanding of the action of PBTZ169 against its target DprE1 is available. A new PBTZ169 combination therapy has been tested in a murine model and shown to be superior to the existing standard of care. Graphical Abstract Tuberculosis (TB) drug resistance is still spreading worldwide, emphasizing the need for new efficient drug combinations. PBTZ169 is here presented as an optimized, potent and synergistic preclinical drug candidate for the treatment of TB in humans.

Marine-derived cyclic imine toxins, portimine A and portimine B, have attracted attention because of their chemical structure and notable anti-cancer therapeutic potential 1 – 4 . However, access to large quantities of these toxins is currently not feasible, and the molecular mechanism underlying their potent activity remains unknown until now. To address this, a scalable and concise synthesis of portimines is presented, which benefits from the logic used in the two-phase terpenoid synthesis 5 , 6 along with other tactics such as exploiting ring-chain tautomerization and skeletal reorganization to minimize protecting group chemistry through self-protection. Notably, this total synthesis enabled a structural reassignment of portimine B and an in-depth functional evaluation of portimine A, revealing that it induces apoptosis selectively in human cancer cell lines with high potency and is efficacious in vivo in tumour-clearance models. Finally, practical access to the portimines and their analogues simplified the development of photoaffinity analogues, which were used in chemical proteomic experiments to identify a primary target of portimine A as the 60S ribosomal export protein NMD3. A scalable total synthesis of portimines enables structural reassignment of portimine B and in-depth functional evaluation of portimine A, revealing that portimine A induces translation inhibition selectively in human cancer cells and is efficacious in vivo tumour-clearance models.

New drugs are required to counter the tuberculosis (TB) pandemic. Here, we describe the synthesis and characterization of 1,3-benzothiazin-4-ones (BTZs), a new class of antimycobacterial agents that kill Mycobacterium tuberculosis in vitro, ex vivo, and in mouse models of TB. Using genetics and biochemistry, we identified the enzyme decaprenylphosphoryl-β-D-ribose 2′-epimerase as a major BTZ target. Inhibition of this enzymatic activity abolishes the formation of decaprenylphosphoryl arabinose, a key precursor that is required for the synthesis of the cell-wall arabinans, thus provoking cell lysis and bacterial death. The most advanced compound, BTZ043, is a candidate for inclusion in combination therapies for both drug-sensitive and extensively drug-resistant TB.