Clinical Pharmacokinetics of Ponesimod, a Selective S1P1 Receptor Modulator, in the Treatment of Multiple Sclerosis.

Ponesimod, a selective, rapidly reversible, and orally active, sphingosine-1 phosphate receptor (S1P) modulator, is indicated for the treatment of relapsing-remitting multiple sclerosis (RRMS). The clinical pharmacokinetics (PK) and pharmacodynamics (PD) of ponesimod was studied in 16 phase I, one phase II, and one phase III clinical studies. Ponesimod population PK was characterized by an open two-compartment disposition model with a terminal half-life of 33 h (accumulation factor of 2- to 2.

Bladder calculi causing irreducible urogenital prolapse.

Over 200 000 surgeries for vaginal prolapse are done annually, and these are rarely urgent. However, when the rare event of bladder stones causes incarcerated procidentia, surgical intervention should not be delayed, due to unrelenting pain and end-organs effects. We present such a case below.

MK-7622: A First-in-Class M Positive Allosteric Modulator Development Candidate.

Identification of ligands that selectively activate the M muscarinic signaling pathway has been sought for decades to treat a range of neurological and cognitive disorders. Herein, we describe the optimization efforts focused on addressing key physicochemical and safety properties, ultimately leading to the clinical candidate MK-7622, a highly selective positive allosteric modulator of the M muscarinic receptor that has entered Phase II studies in patients with Alzheimer's disease.

Do clinicians receive adequate training to identify trafficked persons? A scoping review of NHS Foundation Trusts.

Objective: We investigate whether physicians in secondary care in the English NHS receive adequate training to recognise and appropriately refer for services those persons suspected to be victims of human trafficking.

Design: Freedom of Information requests were sent to the 105 England's NHS Trusts delivering acute care in England.

Setting: NHS Trusts providing secondary care in England.

siRNA-mediated knockdown of P450 oxidoreductase in rats: a tool to reduce metabolism by CYPs and increase exposure of high clearance compounds.

Purpose: To develop a tool based on siRNA-mediated knockdown of hepatic P450 oxidoreductase (POR) to decrease the CYP-mediated metabolism of small molecule drugs that suffer from rapid metabolism in vivo, with the aim of improving plasma exposure of these drugs.

Methods: siRNA against the POR gene was delivered using lipid nanoparticles (LNPs) into rats. The time course of POR mRNA knockdown, POR protein knockdown, and loss of POR enzyme activity was monitored.

Discovery of naphthyl-fused 5-membered lactams as a new class of m1 positive allosteric modulators.

Selective activation of the M1 muscarinic receptor via positive allosteric modulation represents an original approach to treat the cognitive decline in patients with Alzheimer's disease. A series of naphthyl-fused 5-membered lactams were identified as a new class of M1 positive allosteric modulators and were found to possess good potency and in vivo efficacy.

Identification of a methoxynaphthalene scaffold as a core replacement in quinolizidinone amide M(1) positive allosteric modulators.

A series of methoxynaphthalene amides were prepared and evaluated as alternatives to quinolizidinone amide M1 positive allosteric modulators. A methoxy group was optimal for M1 activity and addressed key P-gp issues present in the aforementioned quinolizidinone amide series.

The preclinical efficacy, selectivity and pharmacologic profile of MK-5932, an insulin-sparing selective glucocorticoid receptor modulator.

Glucocorticoids are used widely in the treatment of inflammatory diseases, but use is accompanied by a significant burden of adverse effects. It has been hypothesized that gene- and cell-specific regulation of the glucocorticoid receptor by small molecule ligands could be translated into a therapeutic with an improved risk-benefit profile. MK-5932 is a highly selective glucocorticoid receptor modulator that is anti-inflammatory in vivo with an improved profile on glucose metabolism: Bungard et al.

Orally active fumagillin analogues: transformations of a reactive warhead in the gastric environment.

Semisynthetic analogues of fumagillin, 1, inhibit methionine aminopeptidase-2 (MetAP2) and have entered the clinic for the treatment of cancer. An optimized fumagillin analogue, 3 (PPI-2458), was found to be orally active, despite containing a spiroepoxide function that formed a covalent linkage to the target protein. In aqueous acid, 3 underwent ring-opening addition of water and HCl, leading to four products, 4-7, which were characterized in detail.

Metabolites of PPI-2458, a selective, irreversible inhibitor of methionine aminopeptidase-2: structure determination and in vivo activity.

The natural product fumagillin exhibits potent antiproliferative and antiangiogenic properties. The semisynthetic analog PPI-2458, [(3R,4S,5S,6R)-5-methoxy-4-[(2R,3R)-2-methyl-3-(3-methylbut-2-enyl)oxiran-2-yl]-1-oxaspiro[2.5]octan-6-yl] N-[(2R)-1-amino-3-methyl-1-oxobutan-2-yl]carbamate, demonstrates rapid inactivation of its molecular target, methionine aminopeptidase-2 (MetAP2), and good efficacy in several rodent models of cancer and inflammation with oral dosing despite low apparent oral bioavailability.

Identification of amides as carboxylic Acid surrogates for quinolizidinone-based m1 positive allosteric modulators.

Selective activation of the M1 muscarinic receptor via positive allosteric modulation represents an approach to treat the cognitive decline in patients with Alzheimer's disease. A series of amides were examined as a replacement for the carboxylic acid moiety in a class of quinolizidinone carboxylic acid M1 muscarinic receptor positive allosteric modulators, and leading pyran 4o and cyclohexane 5c were found to possess good potency and in vivo efficacy.

Discovery of selective glucocorticoid receptor modulator MK-5932.

A series of partial agonists of the Glucocorticoid Receptor were prepared targeting reduced transactivation activity, while maintaining significant transrepression activity. Incorporation of an ortho-aryl amide produced compounds with the desired in vitro profile. Bioreactors consisting of Suspension cultures of Sf21 cells co expressing a CYP3A4 and NADPH-cytochrome P450 oxireductase were used to prepare the major metabolites of these compounds and revealed that oxidative N-dealkylation provided a pathway for formation of metabolites that were more agonistic than the parent partial agonists.

Discovery of a selective allosteric M1 receptor modulator with suitable development properties based on a quinolizidinone carboxylic acid scaffold.

One approach to ameliorate the cognitive decline in Alzheimer's disease (AD) has been to restore neuronal signaling from the basal forebrain cholinergic system via the activation of the M(1) muscarinic receptor. A number of nonselective M(1) muscarinic agonists have previously shown positive effects on cognitive behaviors in AD patients, but were limited due to cholinergic adverse events thought to be mediated by the activation of the M(2) to M(5) subtypes. One strategy to confer selectivity for M(1) is the identification of positive allosteric modulators, which would target an allosteric site on the M(1) receptor rather than the highly conserved orthosteric acetylcholine binding site.

Quinolizidinone carboxylic acid selective M1 allosteric modulators: SAR in the piperidine series.

SAR study of the piperidine moiety in a series of quinolizidinone carboxylic acid M(1) positive allosteric modulators was examined. While the SAR was generally flat, compounds were identified with high CNS exposure to warrant additional in vivo evaluation.

Fused heterocyclic M1 positive allosteric modulators.

Fused aromatics such as naphthalene were identified as highly potent and CNS penetrant M(1) positive allosteric modulators during an SAR study to replace the phenyl B-ring linkage.

Quinolizidinone carboxylic acids as CNS penetrant, selective m1 allosteric muscarinic receptor modulators.

Positive allosteric modulation of the M1 muscarinic receptor represents an approach to treat the cognitive decline in patients with Alzheimer's disease. Replacement of a quinolone ring system in a quinolone carboxylic acid series of M1 modulators with a quinolizidinone bearing a basic amine linkage led to a series of compounds with higher free fraction, enhanced CNS exposure, and improved efficacy in rodent in vivo models of cognition.

Hydroxy cycloalkyl fused pyridone carboxylic acid M(1) positive allosteric modulators.

Incorporation of hydroxycycloalkyl fused pyridone carboxylic acids in lieu of quinolone carboxylic acids enhance free fraction without increased susceptibility to P-glycoprotein transport.

Heterocyclic fused pyridone carboxylic acid M(1) positive allosteric modulators.

The phenyl ring in a series of quinolone carboxylic acid M(1) positive allosteric modulators was replaced with a variety of heterocycles in order to reduce protein plasma binding and enhance CNS exposure.

N-heterocyclic derived M1 positive allosteric modulators.

Replacement of a phenyl ring with N-linked heterocycles in a series of quinolone carboxylic acid M1 positive allosteric modulators was investigated. In particular, a pyrazole derivative exhibited improvements in potency, free fraction, and CNS exposure.

Carbamate analogues of fumagillin as potent, targeted inhibitors of methionine aminopeptidase-2.

Inhibition of methionine aminopeptidase-2 (MetAP2) represents a novel approach to antiangiogenic therapy. We describe the synthesis and activity of fumagillin analogues that address the pharmacokinetic and safety liabilities of earlier candidates in this compound class. Two-step elaboration of fumagillol with amines yielded a diverse series of carbamates at C6 of the cyclohexane spiroepoxide.

A novel methionine aminopeptidase-2 inhibitor, PPI-2458, inhibits non-Hodgkin's lymphoma cell proliferation in vitro and in vivo.

Purpose: Fumagillin and related compounds have potent antiproliferative activity through inhibition of methionine aminopeptidase-2 (MetAP-2). It has recently been reported that MetAP-2 is highly expressed in germinal center B cells and germinal center-derived non-Hodgkin's lymphomas (NHL), suggesting an important role for MetAP-2 in proliferating B cells. Therefore, we determined the importance of MetAP-2 in normal and transformed germinal center B cells by evaluating the effects of MetAP-2 inhibition on the form and function of germinal centers and germinal center-derived NHL cells.

Inhibition of melanoma tumor growth by a pharmacological inhibitor of MetAP-2, PPI-2458.

Over the past few decades, melanoma has shown the fastest growing incidence rate of all cancers. This malignancy is clinically defined by its potential to rapidly metastasize, and advanced metastatic melanomas are highly resistant to existing therapeutic regimens. Here, we report that PPI-2458, a novel, orally active agent of the fumagillin class of irreversible methionine aminopeptidase-2 (MetAP-2) inhibitors, potently inhibited the proliferation of B16F10 melanoma cells in vitro, with a growth inhibitory concentration 50% (GI50) of 0.

Methionine aminopeptidases type I and type II are essential to control cell proliferation.

The dependence of cell growth on methionine aminopeptidase (MetAP) function in bacteria and yeast is firmly established. Here we report experimental evidence that the control of cell proliferation in mammalian cells is directly linked and strictly dependent on the activity of both MetAP-1 and MetAP-2. The targeted downregulation of either methionine aminopeptidase MetAP-1 or MetAP-2 protein expression by small interfering RNA (siRNA) significantly inhibited the proliferation of human umbilical vein endothelial cells (HUVEC) (70%-80%), while A549 human lung carcinoma cell proliferation was less inhibited (20%-30%).

A methionine aminopeptidase-2 inhibitor, PPI-2458, for the treatment of rheumatoid arthritis.

The hallmark of rheumatoid arthritis (RA) is the progressive destruction of articular joints, characterized by invasive synovial hyperplasia and pathological neovascularization. Here we report that PPI-2458, a member of the fumagillin class of irreversible methionine aminopeptidase-2 (MetAP-2) inhibitors, potently inhibits the proliferation of human fibroblast-like synoviocytes (HFLS-RA), derived from RA patients, with a growth inhibitory concentration 50 (GI(50)) of 0.04 nM and a maximum inhibition of >95% at 1 nM.

Mechanisms of idiosyncratic drug reactions: the case of felbamate.

Idiosyncratic drug reactions (IDR) are a specific type of drug toxicity characterized by their delayed onset, low incidence and reactive metabolite formation with little, if any, correlation between pharmacokinetics or pharmacodynamics and the toxicological outcome. As the name implies, IDR are unpredictable and often result in the post marketing failure of otherwise useful therapies. Examples of drugs, which have failed as a result of IDR in recent years, include trovafloxacin, zileuton, troglitazone, tolcapone and felbamate.