Small Molecule Reagent specialty pharmaceutical API, advanced i

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Abnormal p38α mitogen-activated protein kinase signaling in dilated cardiomyopathy caused by lamin A/C gene mutation

We previously interrogated the transcriptome in heart tissue from Lmna(H222P/H222P) mice, a mouse model of cardiomyopathy caused by lamin A/C gene (LMNA) mutation, and found that the extracellular signal-regulated kinase 1/2 and Jun N-terminal kinase branches of the mitogen-activated protein (MAP) kinase signaling pathway were abnormally hyperactivated prior to the onset of significant cardiac impairment. We have now used an alternative gene expression analysis tool to reanalyze this transcriptome and identify hyperactivation of a third branch of the MAP kinase cascade, p38α signaling. Biochemical analysis of hearts from Lmna(H222P/H222P) mice showed enhanced p38α activation prior to and after the onset of heart disease as well as in hearts from human subjects with cardiomyopathy caused by LMNA mutations. Treatment of Lmna(H222P/H222P) mice with the p38α inhibitor ARRY-371797 prevented left ventricular dilatation and deterioration of fractional shortening compared with placebo-treated mice but did not block the expression of collagen genes involved in cardiac fibrosis. These results demonstrate that three different branches of the MAP kinase signaling pathway with overlapping consequences are involved in the pathogenesis of cardiomyopathy caused by LMNA mutations. They further suggest that pharmacological inhibition of p38α may be useful in the treatment of this disease.

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Arimoclomol: a potential therapy under development for ALS

Arimoclomol, an amplifier of heat shock protein expression involved in cellular stress response, has emerged as a potential therapeutic candidate in amyotrophic lateral sclerosis (ALS) in recent years. Treatment with arimoclomol was reported to improve survival and muscle function in a mouse model of motor neuron disease. Several single- and multiple-dose safety studies have been completed in healthy control subjects. A 3-month Phase IIa study in people with ALS demonstrated safety at dosages up to 300 mg/day and another study is currently recruiting participants with familial ALS caused by mutations in the superoxide dismutase gene. We review the rationale for testing arimoclomol in sporadic and familial ALS in the context of available safety and pharmacokinetic data. Published and unpublished literature relative to the drug in the past two decades is discussed. The current review attempts to bring together our existing understanding of the actions of arimoclomol with the disease profile of ALS. The pharmacological profile of arimoclomol and the available preclinical data make it a promising therapeutic possibility in ALS.

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Aprocitentan/1103522-45-7

AR9281 inhibits soluble epoxide hydrolase (s-EH), an enzyme that plays a key role in the cytochrome P450 pathway of arachidonic acid metabolism. Nuclear factor alpha B (NF-alphaB) is a transcription factor implicated in cardiac hypertrophy, and can be anti or pro apoptotic under different conditions. Epoxyeicosatrienoic acids (EETs), a product of cytochrome P450 epoxygenase enzyme action, have a variety of anti-hypertensive and anti-inflammatory effects. EETs have a vasodilatory action similar to endothelium derived hyperpolarizing factor and may inhibit NF-alphaB through a currently unknown mechanism. The enzyme s-EH catalyzes the breakdown of EETs to dihydroxyeicosatrienoic acids. AR9281's inhibition of s-EH enhances EETs anti-hypertensive and anti-inflammatory activities by preventing their breakdown by s-EH, as well as inhibiting NF-alphaB.

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Aprocitentan, A Dual Endothelin Receptor Antagonist Under Development for the Treatment of Resistant Hypertension

Aprocitentan (ACT-132577) is an orally active, dual endothelin-1 (ET-1) receptor antagonist that prevents the binding of ET-1 to both ETA/ETB receptors. It is an active metabolite of macitentan (obtained by oxidative depropylation), an orphan drug used for the treatment of pulmonary arterial hypertension. Aprocitentan is highly bound to plasma proteins and is eliminated in both urine and feces. It is well tolerated across all doses (up to 600 mg with single dose and 100 mg once a day at multiple doses). Its pharmacokinetic profile shows a half-life of 44 h, fitting a once-daily dosing regimen with plasma ET-1 concentrations (reflecting ET receptor antagonism), significantly increasing with doses ≥ 25 mg. Only minor differences in exposure between healthy females and males, healthy elderly and adult subjects, fed and fasted conditions, and renal function have been observed.

Aprocitentan in patients with resistant hypertension is currently under investigation in the PRECISION phase III trial (ClinicalTrials identifier: NCT03541174). Nonetheless, results of pre-clinical data and studies in humans support the potential role of aprocitentan in this clinical setting. The absolute blood pressure (BP) reductions with aprocitentan are in the ranges established as a surrogate for reduction in cardiovascular morbidity in hypertension. Significant changes in BP with aprocitentan are observed within 14 days, and its BP-lowering effects have also been documented with ambulatory BP monitoring. Finally, aprocitentan enhances the BP-lowering effects of other antihypertensive drugs, including renin-angiotensin-system blockers. In conclusion, aprocitentan ameliorates the effects of ET-1 and could potentially reduce BP and provide broader cardiovascular protection in patients with resistant hypertension. Available data support the hypothesis that this new agent could expand our antihypertensive arsenal in resistant hypertension, making aprocitentan an attractive candidate for further large-scale trials.

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Anacetrapib and dalcetrapib: two novel cholesteryl ester transfer protein inhibitors

Objective: To evaluate the role of cholesteryl ester transfer protein (CETP) in the cholesterol transport system and review the pharmacology, pharmacokinetic properties, efficacy, and adverse effects of the CETP inhibitors, anacetrapib and dalcetrapib, for the treatment of dyslipidemia.

Data sources: A literature search was conducted in Ovid/MEDLINE (1950 to week 4 December 2010), PubMed/MEDLINE (up to December 2010), EMBASE (2000 to December 2010), and International Pharmaceutical Abstracts (1970 to December 2010) using the MeSH terms and key words anacetrapib, MK 0859, dalcetrapib, and JTT 705. The search was limited to publications in English.

Study selection and data extraction: Studies evaluating the pharmacology, pharmacokinetics, safety, and efficacy of anacetrapib and dalcetrapib for the treatment of dyslipidemia were included. Clinical reviews evaluating the characterization of CETP and its inhibition as a mechanism for reducing cardiovascular risk were also included.

Data synthesis: Anacetrapib and dalcetrapib represent a novel treatment option for patients who have dyslipidemia and low levels of high-density lipoprotein cholesterol (HDL-C). Anacetrapib and dalcetrapib increase HDL-C by inhibiting CETP-mediated transfer of cholesteryl ester and triglyceride. Studies evaluating the safety and efficacy of anacetrapib and dalcetrapib concluded that both agents safely and effectively augment HDL-C. Their mechanism of action, potential for significant raising of HDL-C, once-daily dosing regimen, and favorable lipid-altering effects when added to hydroxymethylglutaryl-CoA reductase inhibitors are key elements. Anacetrapib and dalcetrapib are well tolerated, with mild gastrointestinal complaints reported more than with placebo. Although another CETP inhibitor, torcetrapib, was withdrawn from clinical development secondary to increased morbidity and mortality, neither anacetrapib nor dalcetrapib has demonstrated the adverse off-target effects portrayed with torcetrapib.

Conclusions: Inhibition of CETP by anacetrapib and dalcetrapib represents an encouraging development in the management of dyslipidemia, particularly in patients with low HDL-C levels. Results of future trials are much anticipated, as these will clarify the role of anacetrapib and dalcetrapib in reduction of cardiovascular disease.

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Inhibition of mutant IDH1 decreases D-2-HG levels without affecting tumorigenic properties of chondrosarcoma cell lines

AGI-5198 is a novel R132H-IDH1 inhibitor, identified through a high-throughput screen blocked R132H-IDH1 activity in a dose-dependent manner. 

Mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 are found in a subset of benign and malignant cartilage tumors, gliomas and leukaemias. The mutant enzyme causes the production of D-2-hydroxyglutarate (D-2-HG), affecting CpG island and histone methylation. While mutations in IDH1/2 are early events in benign cartilage tumors, we evaluated whether these mutations play a role in malignant chondrosarcomas. Compared to IDH1/2 wildtype cell lines, chondrosarcoma cell lines harboring an endogenous IDH1 (n=3) or IDH2 mutation (n=2) showed up to a 100-fold increase in intracellular and extracellular D-2-HG levels. Specific inhibition of mutant IDH1 using AGI-5198 decreased levels of D-2-HG in a dose dependent manner. After 72 hours of treatment one out of three mutant IDH1 cell lines showed a moderate decrease in viability , while D-2-HG levels decreased >90%. Likewise, prolonged treatment (up to 20 passages) did not affect proliferation and migration. Furthermore, global gene expression, CpG island methylation as well as histone H3K4, -9, and -27 trimethylation levels remained unchanged. Thus, while IDH1/2 mutations cause enchondroma, malignant progression towards central chondrosarcoma renders chondrosarcoma growth independent of these mutations. Thus, monotherapy based on inhibition of mutant IDH1 appears insufficient for treatment of inoperable or metastasized chondrosarcoma patients.

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ANAVEX®2-73 (blarcamesine), a Sigma-1 receptor agonist, ameliorates neurologic impairments in a mouse model of Rett syndrome

Rett syndrome (RTT) is a severe neurodevelopmental disorder that is associated in most cases with mutations in the transcriptional regulator MECP2. At present, there are no effective treatments for the disorder. Despite recent advances in RTT genetics and neurobiology, most drug development programs have focused on compounds targeting the IGF-1 pathway and no pivotal trial has been completed as yet.

Thus, testing novel drugs that can ameliorate RTT's clinical manifestations is a high priority.

ANAVEX2-73 (blarcamesine) is a Sigma-1 receptor agonist and muscarinic receptor modulator with a strong safety record and preliminary evidence of efficacy in patients with Alzheimer's disease.

Its role in calcium homeostasis and mitochondrial function, cellular functions that underlie pathological processes and compensatory mechanisms in RTT, makes blarcamesine an intriguing drug candidate for this disorder. Mice deficient in MeCP2 have a range of physiological and neurological abnormalities that mimic the human syndrome.

We tested blarcamesine in female heterozygous mice carrying one null allele of Mecp2 (HET) using a two-tier approach, with age-appropriate tests. Administration of the drug to younger and older adult mice resulted in improvement in multiple motor, sensory, and autonomic phenotypes of relevance to RTT.

The latter included motor coordination and balance, acoustic and visual responses, hindlimb clasping, and apnea in expiration. In line with previous animal and human studies, blarcamesine also showed a good safety profile in this mouse model of RTT. Clinical studies in RTT with blarcamesine are ongoing.

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Preclinical evaluation of AMG 925, a FLT3/CDK4 dual kinase inhibitor for treating acute myeloid leukemia

Acute myeloid leukemia (AML) remains a serious unmet medical need. Despite high remission rates with chemotherapy standard-of-care treatment, the disease eventually relapses in a major proportion of patients.

Activating Fms-like tyrosine kinase 3 (FLT3) mutations are found in approximately 30% of patients with AML. Targeting FLT3 receptor tyrosine kinase has shown encouraging results in treating FLT3-mutated AML. Responses, however, are not sustained and acquired resistance has been a clinical challenge.

Treatment options to overcome resistance are currently the focus of research. We report here the preclinical evaluation of AMG 925, a potent, selective, and bioavailable FLT3/cyclin-dependent kinase 4 (CDK4) dual kinase inhibitor. AMG 925 inhibited AML xenograft tumor growth by 96% to 99% without significant body weight loss.

The antitumor activity of AMG 925 correlated with the inhibition of STAT5 and RB phosphorylation, the pharmacodynamic markers for inhibition of FLT3 and CDK4, respectively. In addition, AMG 925 was also found to inhibit FLT3 mutants (e.g., D835Y) that are resistant to the current FLT3 inhibitors (e.g., AC220 and sorafenib).

CDK4 is a cyclin D-dependent kinase that plays an essential central role in regulating cell proliferation in response to external growth signals. A critical role of the CDK4-RB pathway in cancer development has been well established. CDK4-specific inhibitors are being developed for treating RB-positive cancer. AMG 925, which combines inhibition of two kinases essential for proliferation and survival of FLT3-mutated AML cells, may improve and prolong clinical responses.

AMG-925 is a potent and orally bioavailable dual inhibitor of CDK4 and FLT3, including many FLT3 mutants reported to date. It inhibits the proliferation of a panel of human tumor cell lines including Colo205 (Rb(+)) and U937 (FLT3(WT)) and induced cell death in MOLM13 (FLT3(ITD)) and even in MOLM13 (FLT3(ITD, D835Y)), which exhibits resistance to a number of FLT3 inhibitors currently under clinical development. At well-tolerated doses, AMG 925 leads to significant growth inhibition of MOLM13 xenografts in nude mice, and the activity correlates with inhibition of STAT5 and Rb phosphorylation.