Christoph Boss

Pharmacology of Macitentan, an Orally Active Tissue-Targeting Dual Endothelin Receptor Antagonist

Macitentan, also called Actelion-1 or ACT-064992 [N-[5-(4-bromophenyl)-6-(2-(5-bromopyrimidin-2-yloxy)ethoxy)-pyrimidin-4-yl]-N′-propylaminosulfonamide], is a new dual ETA/ETB endothelin (ET) receptor antagonist designed for tissue targeting. Selection of macitentan was based on inhibitory potency on both ET receptors and optimization of physicochemical properties to achieve high affinity for lipophilic milieu. In vivo, macitentan is metabolized into a major and pharmacologically active metabolite, ACT-132577. Macitentan and its metabolite antagonized the specific binding of ET-1 on membranes of cells overexpressing ETA and ETB receptors and blunted ET-1-induced calcium mobilization in various natural cell lines, with inhibitory constants within the nanomolar range. In functional assays, macitentan and ACT-132577 inhibited ET-1-induced contractions in isolated endothelium-denuded rat aorta (ETA receptors) and sarafotoxin S6c-induced contractions in isolated rat trachea (ETB receptors). In rats with pulmonary hypertension, macitentan prevented both the increase of pulmonary pressure and the right ventricle hypertrophy, and it markedly improved survival. In diabetic rats, chronic administration of macitentan decreased blood pressure and proteinuria and prevented end-organ damage (renal vascular hypertrophy and structural injury). In conclusion, macitentan, by its tissue-targeting properties and dual antagonism of ET receptors, protects against end-organ damage in diabetes and improves survival in pulmonary hypertensive rats. This profile makes macitentan a new agent to treat cardiovascular disorders associated with chronic tissue ET system activation.

The Discovery of N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N′-propylsulfamide (Macitentan), an Orally Active, Potent Dual Endothelin Receptor Antagonist

Starting from the structure of bosentan (1), we embarked on a medicinal chemistry program aiming at the identification of novel potent dual endothelin receptor antagonists with high oral efficacy. This led to the discovery of a novel series of alkyl sulfamide substituted pyrimidines. Among these, compound 17 (macitentan, ACT-064992) emerged as particularly interesting as it is a potent inhibitor of ET(A) with significant affinity for the ET(B) receptor and shows excellent pharmacokinetic properties and high in vivo efficacy in hypertensive Dahl salt-sensitive rats. Compound 17 successfully completed a long-term phase III clinical trial for pulmonary arterial hypertension.

Biomedical application of orexin/hypocretin receptor ligands in neuroscience.

Orexin/hypocretin neuropeptides (orexin-A or hypocretin1 and orexin-B or hypocretin2) are peptides discovered and published in 1998 by two independent research groups as the outcome of methodical deorphanization programs focusing on brain orphan G-protein-coupled receptors (GPCR). Orexins/hypocretins bind to two receptors (orexin1/OX1 or HCRT1 and orexin2/OX2 or HCRT2 receptors) and are proteolytically derived from a single precursor peptide in a discrete population of neurons of the perifornical area of the lateral hypothalamus. OX1 receptors have preferential affinity for orexin-A, whereas OX2 receptors do not discriminate between both neuropeptides in vitro. OX1 or OX2 activation produces intracellular Ca2+ increases via functional coupling involving a Gq or Go mechanism of transduction. This ultimately results in slow membrane depolarization and in neuronal activation found to involve different ionic conductance in various brain regions in the rat, such as potassium conductance in the locus coeruleus or calcium current in the tuberomammilary nucleus. The orexin system is well conserved across mammalian species. Orexin-A is conserved in rat, mouse, pig, dog, and man and contains two disulfide bridges. Orexin-B in rat and mouse differs by only one amino acid (S18N) from porcine, canine, and human orexin-B; it is a linear, nonlipophilic, less stable peptide than orexinA. Both orexins are derived from a single precursor peptide coded on human chromosome 17q21-24, which is syntenic with mouse chromosome 11. High structural and functional homology is also reported for rat and human OX1 and OX2 receptors. The in vitro pharmacology of human and rat orthologues of OX1 is very similar. The human OX1 receptor is coded on chromosome 1p33 and contains seven exons; the human OX2 receptor is coded on chromosome 6p11-q11 containing seven exons over 108 439 base pairs. In the mouse, splice variants of OX2 are distributed in a tissue-specific manner.

X-ray Structure of Plasmepsin II Complexed with a Potent Achiral Inhibitor

The malaria parasite Plasmodium falciparum degrades host cell hemoglobin inside an acidic food vacuole during the blood stage of the infectious cycle. A number of aspartic proteinases called plasmepsins (PMs) have been identified to play important roles in this degradation process and therefore generated significant interest as new antimalarial targets. Several x-ray structures of PMII have been described previously, but thus far, structure-guided drug design has been hampered by the fact that only inhibitors comprising a statine moiety or derivatives thereof have been published. Our drug discovery efforts to find innovative, cheap, and easily synthesized inhibitors against aspartic proteinases yielded some highly potent non-peptidic achiral inhibitors. A highly resolved (1.6 Å) x-ray structure of PMII is presented, featuring a potent achiral inhibitor in an unprecedented orientation, contacting the catalytic aspartates indirectly via the “catalytic” water. Major side chain rearrangements in the active site occur, which open up a new pocket and allow a new binding mode of the inhibitor. Moreover, a second inhibitor molecule could be located unambiguously in the active site of PMII. These newly obtained structural insights will further guide our attempts to improve compound properties eventually leading to the identification of molecules suitable as antimalarial drugs.

Orexin Receptor Antagonists: A New Concept In CNS Disorders?

The orexin (hypocretin) system is an evolutionarily conserved neuropeptide–GPCR system functioning even in vertebrate fish. After a decade of intensive work, it appears that the orexin system plays a crucial role as homeostatic sensor of the body’s external and internal environment and regulates states of wakefulness to facilitate survival. In the brain, it acts as a central regulator of wakefulness and modulates emotional states related to, for example, stress or reward. In accordance with their role in the central nervous system (CNS), these peptide ligands and their associated receptors are expressed in neurons. However, orexins and their receptors can also be found in non-neuronal cells and tissues. The molecular signaling biology of the orexins and their receptors is quite diverse.

Discovery and characterization of ACT-335827, an orally available, brain penetrant orexin receptor type 1 selective antagonist.

Stress relief: Orexin neuropeptides regulate arousal and stress processing through orexin receptor type 1 (OXR-1) and 2 (OXR-2) signaling. A selective OXR-1 antagonist, represented by a phenylglycine-amide substituted tetrahydropapaverine derivative (ACT-335827), is described that is orally available, penetrates the brain, and decreases fear, compulsive behaviors and autonomic stress reactions in rats.

Design and Preparation of Potent, Nonpeptidic, Bioavailable Renin Inhibitors

Starting from known piperidine renin inhibitors, a new series of 3,9-diazabicyclo[3.3.1]nonene derivatives was rationally designed and prepared. Optimization of the positions 3, 6, and 7 of the diazabicyclonene template led to potent renin inhibitors. The substituents attached at the positions 6 and 7 were essential for the binding affinity of these compounds for renin. The introduction of a substituent attached at the position 3 did not modify the binding affinity but allowed the modulation of the ADME properties. Our efforts led to the discovery of compound (+)-26g that inhibits renin with an IC(50) of 0.20 nM in buffer and 19 nM in plasma. The pharmacokinetics properties of this and other similar compounds are discussed. Compound (+)-26g is well absorbed in rats and efficacious at 10 mg/kg in vivo.

N-Glycine-sulfonamides as potent dual orexin 1/orexin 2 receptor antagonists.

A series of dual OX(1)R/OX(2)R orexin antagonists was prepared based on a N-glycine-sulfonamide core. SAR studies of a screening hit led to compounds with low nanomolar affinity for both receptors and good oral bioavailability. One of these compounds, 47, has demonstrated in vivo activity in rats following oral administration.

Recent trends in orexin research—2010 to 2015

Specific neurons in the lateral hypothalamus produce the orexin neuropeptides (orexin-A and orexin-B). The orexin-peptides are transported to areas of the brain regulating sleep-wake cycles, controlling food intake or modulating emotional states such as panic or anxiety. The orexin system, consisting of the two orexin-neuropeptides and two G-protein-coupled receptors (the orexin-1 and the orexin-2 receptor) is as well involved in reward and addictive behaviors. The review reflects on the most recent activities in the field of orexin research.

Identification of a New Chemical Class of Antimalarials

The increasing spread of drug-resistant malaria strains underscores the need for new antimalarial agents with novel modes of action (MOAs). Here, we describe a compound representative of a new class of antimalarials. This molecule, ACT-213615, potently inhibits in vitro erythrocytic growth of all tested Plasmodium falciparum strains, irrespective of their drug resistance properties, with half-maximal inhibitory concentration (IC(50)) values in the low single-digit nanomolar range. Like the clinically used artemisinins, the compound equally and very rapidly affects all 3 asexual erythrocytic parasite stages. In contrast, microarray studies suggest that the MOA of ACT-213615 is different from that of the artemisinins and other known antimalarials. ACT-213615 is orally bioavailable in mice, exhibits activity in the murine Plasmodium berghei model and efficacy comparable to that of the reference drug chloroquine in the recently established P. falciparum SCID mouse model. ACT-213615 represents a new class of potent antimalarials that merits further investigation for its clinical potential.