Selecting an Anti-Malarial Clinical Candidate from Two Potent Dihydroisoquinolones

BACKGROUND: The ongoing global malaria eradication campaign requires development of potent, safe, and cost-effective drugs lacking cross-resistance with existing chemotherapies. One critical step in drug development is selecting a suitable clinical candidate from late leads. The process used to select the clinical candidate SJ733 from two potent dihydroisoquinolone (DHIQ) late leads, SJ733 and SJ311, based on their physicochemical, pharmacokinetic (PK), and toxicity profiles is described. METHODS: The compounds were tested to define their physicochemical properties including kinetic and thermodynamic solubility, partition coefficient, permeability, ionization constant, and binding to plasma proteins. Metabolic stability was assessed in both microsomes and hepatocytes derived from mice, rats, dogs, and humans. Cytochrome P450 inhibition was assessed using recombinant human cytochrome enzymes. The pharmacokinetic profiles of single intravenous or oral doses were investigated in mice, rats, and dogs. RESULTS: Although both compounds displayed similar physicochemical properties, SJ733 was more permeable but metabolically less stable than SJ311 in vitro. Single dose PK studies of SJ733 in mice, rats, and dogs demonstrated appreciable oral bioavailability (60-100%), whereas SJ311 had lower oral bioavailability (mice 23%, rats 40%) and higher renal clearance (10-30 fold higher than SJ733 in rats and dogs), suggesting less favorable exposure in humans. SJ311 also displayed a narrower range of dose-proportional exposure, with plasma exposure flattening at doses above 200 mg/kg. CONCLUSION: SJ733 was chosen as the candidate based on a more favorable dose proportionality of exposure and stronger expectation of the ability to justify a strong therapeutic index to regulators

Positive allosteric modulation of the muscarinic M1 receptor improves efficacy of antipsychotics in mouse glutamatergic deficit models of behavior

Current antipsychotics are effective in treating the positive symptoms associated with schizophrenia, but they remain suboptimal in targeting cognitive dysfunction. Recent studies have suggested that positive allosteric modulation of the M1 muscarinic acetylcholine receptor (mAChR) may provide a novel means of improving cognition. However, very little is known about the potential of combination therapies in extending coverage across schizophrenic symptom domains. This study investigated the effect of the M1 mAChR positive allosteric modulator BQCA [1-(4-methoxybenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid], alone or in combination with haloperidol (a first-generation antipsychotic), clozapine (a second-generation atypical antipsychotic), or aripiprazole (a third-generation atypical antipsychotic), in reversing deficits in sensorimotor gating and spatial memory induced by the N-methyl-d-aspartate receptor antagonist, MK-801 [(5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine]. Sensorimotor gating and spatial memory induction are two models that represent aspects of schizophrenia modeled in rodents. In prepulse inhibition (an operational measure of sensorimotor gating), BQCA alone had minimal effects but exhibited different levels of efficacy in reversing MK-801–induced prepulse inhibition disruptions when combined with a subeffective dose of each of the three (currently prescribed) antipsychotics. Furthermore, the combined effect of BQCA and clozapine was absent in M1−/− mice. Interestingly, although BQCA alone had no effect in reversing MK-801–induced memory impairments in a Y-maze spatial test, we observed a reversal upon the combination of BQCA with atypical antipsychotics, but not with haloperidol. These findings provide proof of concept that a judicious combination of existing antipsychotics with a selective M1 mAChR positive allosteric modulator can extend antipsychotic efficacy in glutamatergic deficit models of behavior

Revisiting the SAR of the antischistosomal aryl hydantoin (Ro 13-3978)

The aryl hydantoin 1 (Ro 13-3978) was identified in the early 1980s as a promising antischistosomal lead compound. However, this series of aryl hydantoins produced antiandrogenic side effects in the host, a not unexpected outcome given their close structural similarity to the antiandrogenic drug nilutamide. Building on the known SAR of this compound series, we now describe a number of analogs of 1 designed to maximize structural diversity guided by incorporation of substructures and functional groups known to diminish ligand-androgen receptor interactions. These analogs had calculated polar surface area (PSA), measured LogD7.4, aqueous kinetic solubility, and estimated plasma protein binding values in ranges predictive of good ADME profiles. The principal SAR insight was that the hydantoin core of 1 is required for high antischistosomal activity. We identified several compounds with high antischistosomal efficacy that were less antiandrogenic than 1. These data provide direction for the ongoing optimization of antischistosomal hydantoins

Effect of Self-monitoring and Medication Self-titration on Systolic Blood Pressure in Hypertensive Patients at High Risk of Cardiovascular Disease

IMPORTANCE: Self-monitoring of blood pressure with self-titration of antihypertensives (self-management) results in lower blood pressure in patients with hypertension, but there are no data about patients in high-risk groups. OBJECTIVE: To determine the effect of self-monitoring with self-titration of antihypertensive medication compared with usual care on systolic blood pressure among patients with cardiovascular disease, diabetes, or chronic kidney disease. DESIGN, SETTING, AND PATIENTS: A primary care, unblinded, randomized clinical trial involving 552 patients who were aged at least 35 years with a history of stroke, coronary heart disease, diabetes, or chronic kidney disease and with baseline blood pressure of at least 130/80 mm Hg being treated at 59 UK primary care practices was conducted between March 2011 and January 2013. INTERVENTIONS: Self-monitoring of blood pressure combined with an individualized self-titration algorithm. During the study period, the office visit blood pressure measurement target was 130/80 mm Hg and the home measurement target was 120/75 mm Hg. Control patients received usual care consisting of seeing their health care clinician for routine blood pressure measurement and adjustment of medication if necessary. MAIN OUTCOMES AND MEASURES: The primary outcome was the difference in systolic blood pressure between intervention and control groups at the 12-month office visit. RESULTS: Primary outcome data were available from 450 patients (81%). The mean baseline blood pressure was 143.1/80.5 mm Hg in the intervention group and 143.6/79.5 mm Hg in the control group. After 12 months, the mean blood pressure had decreased to 128.2/73.8 mm Hg in the intervention group and to 137.8/76.3 mm Hg in the control group, a difference of 9.2 mm Hg (95% CI, 5.7-12.7) in systolic and 3.4 mm Hg (95% CI, 1.8-5.0) in diastolic blood pressure following correction for baseline blood pressure. Multiple imputation for missing values gave similar results: the mean baseline was 143.5/80.2 mm Hg in the intervention group vs 144.2/79.9 mm Hg in the control group, and at 12 months, the mean was 128.6/73.6 mm Hg in the intervention group vs 138.2/76.4 mm Hg in the control group, with a difference of 8.8 mm Hg (95% CI, 4.9-12.7) for systolic and 3.1 mm Hg (95% CI, 0.7-5.5) for diastolic blood pressure between groups. These results were comparable in all subgroups, without excessive adverse events. CONCLUSIONS AND RELEVANCE: Among patients with hypertension at high risk of cardiovascular disease, self-monitoring with self-titration of antihypertensive medication compared with usual care resulted in lower systolic blood pressure at 12 months

PPARα and PPARγ activation is associated with pleural mesothelioma invasion but therapeutic inhibition is ineffective

Mesothelioma is a cancer that typically originates in the pleura of the lungs. It rapidly invades the surrounding tissues, causing pain and shortness of breath. We compared cell lines injected either subcutaneously or intrapleurally and found that only the latter resulted in invasive and rapid growth. Pleural tumors displayed a transcriptional signature consistent with increased activity of nuclear receptors PPARα and PPARγ and with an increased abundance of endogenous PPAR-activating ligands. We found that chemical probe GW6471 is a potent, dual PPARα/γ antagonist with anti-invasive and anti-proliferative activity in vitro. However, administration of GW6471 at doses that provided sustained plasma exposure levels sufficient for inhibition of PPARα/γ transcriptional activity did not result in significant anti-mesothelioma activity in mice. Lastly, we demonstrate that the in vitro anti-tumor effect of GW6471 is off-target. We conclude that dual PPARα/γ antagonism alone is not a viable treatment modality for mesothelioma

Development of novel 4‐arylpyridin‐2‐one and 6‐arylpyrimidin‐4‐one positive allosteric modulators of the M1 muscarinic acetylcholine receptor

This study investigated the structure‐activity relationships of 4‐phenylpyridin‐2‐one and 6‐phenylpyrimidin‐4‐one muscarinic M1 acetylcholine receptor (M1 mAChRs) positive allosteric modulators (PAMs). The presented series focuses on modifications to the core and top motif of the reported leads, MIPS1650 (1) and MIPS1780 (2). Profiling of our novel analogues showed that these modifications result in more nuanced effects on the allosteric properties compared to our previous compounds with alterations to the biaryl pendant. Further pharmacological characterisation of the selected compounds in radioligand binding, IP1 accumulation and β‐arrestin 2 recruitment assays demonstrated that despite primarily acting as affinity modulators, the PAMs displayed different pharmacological properties across the two cellular assays. The novel PAM 7f is a potential lead candidate for further development of peripherally‐restricted M1 PAMs, due to its lower blood‐brain‐barrier (BBB) permeability and improved exposure in the periphery compared to lead 2

Carvedilol blocks neural regulation of breast cancer progression in vivo and is associated with reduced breast cancer mortality in patients

© 2021 Elsevier Ltd Purpose: The sympathetic nervous system drives breast cancer progression through β-adrenergic receptor signalling. This discovery has led to the consideration of cardiac β-blocker drugs as novel strategies for anticancer therapies. Carvedilol is a β-blocker used in the management of cardiovascular disorders, anxiety, migraine and chemotherapy-induced cardiotoxicity. However, little is known about how carvedilol affects cancer-related outcomes. Methods: To address this, we investigated the effects of carvedilol on breast cancer cell lines, in mouse models of breast cancer and in a large cohort of patients with breast cancer (n = 4014). Results: Treatment with carvedilol blocked the effects of sympathetic nervous system activation, reducing primary tumour growth and metastasis in a mouse model of breast cancer and preventing invasion by breast cancer cell lines. A retrospective analysis found that women using carvedilol at breast cancer diagnosis (n = 136) had reduced breast cancer-specific mortality compared with women who did not (n = 3878) (5-year cumulative incidence of breast cancer deaths: 3.1% versus 5.7%; p = 0.024 and 0.076 from univariate and multivariable analyses, respectively) after a median follow-up of 5.5 years. Conclusions: These findings provide a rationale to further explore the use of the β-blocker carvedilol as a novel strategy to slow cancer progression

Preclinical data do not support the use of amiodarone or dronedarone as antiparasitic drugs for Chagas disease at the approved human dosing regimen

The repurposing of approved drugs is an appealing method to fast-track the development of novel therapies for neglected diseases. Amiodarone and dronedarone, two approved antiarrhythmic agents, have been reported to have potential for the management of Chagas disease patients displaying symptomatic heart pathology. More recently, it has been suggested that both molecules not only have an antiarrhythmic effect, but also have trypanocidal activity against Trypanosoma cruzi, the causative agent of Chagas disease. In this work, we assessed the in vitro activity of these compounds against T. cruzi, the in vivo pharmacokinetics, and pharmacodynamics, to determine the potential for repurposing these drugs as therapies for Chagas disease. Based on these results, we were unable to reproduce the in vitro potencies of amiodarone and dronedarone described in the literature, and both drugs were found to be inactive or cytotoxic against a variety of different mammalian cell lines. The evaluation of in vivo efficacy in a bioluminescent murine model of T. cruzi did not show antiparasitic activity at the highest tolerated dose tested. While the potential of amiodarone and dronedarone as antiarrhythmic agents in Chagas cardiomyopathic patients cannot be completely excluded, a trypanocidal effect in patients treated with these two drugs appears unlikely

DNDI-6174 is a preclinical candidate for visceral leishmaniasis that targets the cytochrome bc1

New drugs for visceral leishmaniasis that are safe, low cost, and adapted to the field are urgently required. Despite concerted efforts over the last several years, the number of new chemical entities that are suitable for clinical development for the treatment of Leishmania remains low. Here, we describe the discovery and preclinical development of DNDI-6174, an inhibitor of Leishmania cytochrome bc1 complex activity that originated from a phenotypically identified pyrrolopyrimidine series. This compound fulfills all target candidate profile criteria required for progression into preclinical development. In addition to good metabolic stability and pharmacokinetic properties, DNDI-6174 demonstrates potent in vitro activity against a variety of Leishmania species and can reduce parasite burden in animal models of infection, with the potential to approach sterile cure. No major flags were identified in preliminary safety studies, including an exploratory 14-day toxicology study in the rat. DNDI-6174 is a cytochrome bc1 complex inhibitor with acceptable development properties to enter preclinical development for visceral leishmaniasis.</p

DNDI-6174 is a preclinical candidate for visceral leishmaniasis that targets the cytochrome bc1

New drugs for visceral leishmaniasis that are safe, low cost, and adapted to the field are urgently required. Despite concerted efforts over the last several years, the number of new chemical entities that are suitable for clinical development for the treatment of Leishmania remains low. Here, we describe the discovery and preclinical development of DNDI-6174, an inhibitor of Leishmania cytochrome bc1 complex activity that originated from a phenotypically identified pyrrolopyrimidine series. This compound fulfills all target candidate profile criteria required for progression into preclinical development. In addition to good metabolic stability and pharmacokinetic properties, DNDI-6174 demonstrates potent in vitro activity against a variety of Leishmania species and can reduce parasite burden in animal models of infection, with the potential to approach sterile cure. No major flags were identified in preliminary safety studies, including an exploratory 14-day toxicology study in the rat. DNDI-6174 is a cytochrome bc1 complex inhibitor with acceptable development properties to enter preclinical development for visceral leishmaniasis.</p