Serine palmitoyltransferase inhibitors for the treatment of obesity

Abstract

According to a first aspect, the invention relates to a pharmaceutical composition prepared for oral administration for the treatment of obesity, comprising an active ingredient which inhibits serine palmitoyltransferase (EC 2.1.3.50). Another aspect of the invention relates to the use of myriocin for the treatment of obesity.

Description

[0001] The invention relates to the use of serine palmitoyltransferase (SPT) inhibitors that accumulate in the intestine and the microbiome for the treatment of obesity, particularly by oral administration. The group of active substances usable according to the invention includes, in particular, the substance myriocin (CAS 35891-70-4), also known as ISP-1 and thermozymocidin, which occurs naturally in the fungus of the genus Cordyceps. Background of the invention

[0002] There are currently no reliable methods for weight loss beyond very serious procedures such as partial gastrectomy. Recent studies suggest that GLP-1 analogs may be used for weight loss in patients with diabetes and obesity. This naturally occurring gut hormone is administered by injection and, at the highest dose, can lead to a weight reduction of up to 17% within a few months. However, most patients suffer from gastrointestinal disorders.

[0003] All appetite suppressants have been withdrawn from the market in recent years due to severe side effects (drug dependence). Therefore, no orally available weight-loss medications are currently available. Partial gastrectomy is a major surgical procedure with correspondingly significant limitations for patients. This treatment is therefore only considered in very severe cases. Treatment with GLP-1 analogs is currently only approved for diabetic patients. The substance must be injected. Furthermore, it is a hormone treatment that has far-reaching consequences for the patient's metabolism and causes numerous side effects. The effect, however, is limited to a maximum weight loss of 17% at the highest administered dose.

[0004] Weight regulation is not only dependent on the host but can also be significantly influenced by the gut microbiome. For example, colonization of the gut of germ-free mice with the microbiome of obese mice was associated with a significant increase in body weight, while conversely, colonization with the microbiome of lean mice was associated with weight loss. A possible function of SPT in this context is unclear. However, germ-free mice whose gut was colonized with an SPT-deficient Bacteroides thetaiotaomicron bacterial strain developed fulminant intestinal inflammation [1]. Thus, according to current literature, inhibition of SPT in the microbiome is rather contraindicated for use with the aim of achieving weight reduction with minimal side effects.

[0005] Myriocin was first described in 1971 as an antifungal agent of the thermophilic fungus Myriococcum albomyces against the fungus Candida albicans (Kluepfel et al. J Antibiot (Tokyo), 1972. 25(2): p. 109-15). While it showed high toxicity after injection (mean lethal dose LD50) 50 (Intraperitoneal injection of 5-10 mg / kg in mice, 2-5 mg / kg in rats, and death of dogs 48-72 h after subcutaneous injection of 0.25 mg / kg) resulted in the following: oral administration of myriocin with a mean lethal dose LD50 50Myriocin is very well tolerated at doses of 300-400 mg / kg. The authors suspected poor absorption of myriocin after oral administration as the reason. The same substance was subsequently isolated from thermophilic eumycetes (Aragozzini et al. Experientia, 1972. 28(8): p. 881-2; Craveri et al. Experientia, 1972. 28(7): p. 867-8). Myriocin was rediscovered in 1994 under the name ISP-1 from the ascomycete fungus Isaria sinclairii of the genus Cordyceps, exhibiting immunosuppressive activity (Fujita et al. J Antibiot (Tokyo), 1994. 47(2): p. 208-15). Shortly thereafter, myriocin was identified as an inhibitor of serine palmitoyltransferase (SPT) (Miyake et al. Biochem Biophys Res Commun, 1995. 211(2): p. 396-403). Since then, myriocin has been used as an inhibitor of sphingolipid de novo synthesis, with most studies employing administration by injection.Various publications on systemic administration via injection or infusion showed highly heterogeneous effects on a wide range of diseases, including diabetes, arteriosclerosis, neurodegeneration, obesity, and others. The effects on body weight in these 58 publications were inconclusive. Some studies suggested reduced weight gain in the animals (Dekker et al. Atherosclerosis, 2013. 228(1): p. 98-109; Kurek et al. J Diabetes Res, 2015. 2015: p. 154762; Kurek et al. Liver Int, 2014. 34(7): p. 1074-83; Kurek et al. Biomed Res Int, 2014. 2014: p. 980815; Picard et al. Mol Metab, 2014. 3(2): p. 167-76; Salaun et al. J Appl Physiol (1985), 2016. 120(2): p. 178-87; Yang et al. Am J Physiol Endocrinol Metab, 2009. 297(1): p. E211-24), others showed no differences (Campana et al. Mol Metab, 2018. 8: p. 23-36; Handzlik et al. Nature, 2023. 614(7946): p. 118-124; Ussher et al. Diabetes, 2010. 59(10): p. 2453-64).Only one study indicates slight weight loss (Kurek et al. Adv Med Sci, 2017. 62(1): p. 65-73). Due to systemic administration, the effects are generally not comparable to the invention described here, as these routes of administration do not result in specific accumulation of the SPT inhibitor myriocin in the gut and microbiome. The results are similar in the 21 studies that used an oral route of administration. Five studies showed no effect on body weight (Chen et al. Am J Physiol Endocrinol Metab, 2018. 315(3): p. E416-E424; Kasumov et al. Arterioscler Thromb Vasc Biol, 2013. 33(8): p. 1994-2003; Lee et al. J Gastroenterol Hepatol, 2010. 25(6): p. 1105-10; Park et al. J Lipid Res, 2008. 49(10): p. 2101-12; Yu et al. Clin Sci (Lond), 2020. 134(5): p. 439-458), while five studies showed reduced weight gain (Glaros et al. J Lipid Res, 2008. 49(2): p. 324-31). ; Ji et al. JCI Insight, 2017. 2(9); Kasumov et al. PLoS One, 2015. 10(5): p.e0126910; Petit et al. Proc Natl Acad Sci USA, 2020. 117(19): p. 10565-10574 ; Yang et al. Lipids Health Dis, 2019. 18(1): p. 179) and a single study shows slight weight loss (Woo et al. Diabetes Metab J, 2020. 44(4): p. 581-591).

[0006] None of these studies indicate a dose-dependent weight loss in the animals, although the administered concentrations were comparable to the concentrations of myriocin used here and in some cases treatment lasted for a significantly longer period of 8 to 12 weeks.

[0007] Myriocin is a metabolite that can be extracted from fungi. Powdered mushrooms and ethanolic extracts and concentrates thereof are also used in naturopathy. Myriocin has also been detected as a component in corresponding extracts and powders of the genus Cordyceps. In one study, the administration of myriocin-containing mushroom extract led to reduced weight gain, but no weight loss, in mice on a high-fat diet over 12 weeks. The amount of food consumed was not documented, and therefore lower food intake could also be the cause of the reduced weight gain (Li et al. Sci Rep, 2022. 12(1): p. 7273). The actual amount of myriocin ingested in this study was less than 8 ng / kg body weight per day, which is more than 375 times lower than the concentrations used here.This means that the effect described here cannot be achieved through oral administration of Cordyceps mushroom products.

[0008] Myriocin is associated with the use of various medical conditions; however, to the inventors' knowledge, there is no evidence of a general dose-dependent use for induced weight loss independent of disease states. Likewise, there is no evidence of myriocin accumulating in the gut and the microbiome, which is essential for the specific use described here for dose-dependent, low-side-effect weight reduction. Summary of the invention

[0009] According to a first aspect, the invention relates to a pharmaceutical composition prepared for oral administration for the treatment of obesity, comprising an active ingredient which inhibits serine palmitoyltransferase (EC 2.1.3.50).

[0010] Another aspect of the invention relates to the use of myriocin for the treatment of obesity. Description of the illustrations Fig. : Weight loss with increasing concentration (mg / kg / day) of myriocin (ISP-1) in C57BL / 6 wild-type mice. Fig. : Concentration of myriocin (ISP-1) in the small intestine and large intestine after oral or intraperitoneal administration of 0.3 mg / kg / day myriocin. Fig. : Concentration of myriocin (ISP-1) in the microbiome after oral or intraperitoneal administration of 0.3 mg / kg / day myriocin. Fig. : Concentration of myriocin (ISP-1) in liver and spleen after oral or intraperitoneal administration of 0.3 mg / kg / day myriocin. Fig. Weight monitoring after intraperitoneal administration of 0.3 mg / kg / day myriocin (ISP-1) over a period of 6 weeks in apolipoprotein E (ApoE)-deficient mice fed a high-fat Western diet. No weight loss was observed. Fig. : Examination of the large intestine of untreated and mice treated with 1 mg / kg / day myriocin for possible intestinal inflammation. Fig. : Example of a 4 µm tissue section of the large intestine of an untreated C57BL / 6 mouse. Fig. : Example of a 4 µm tissue section of the colon of a C57BL / 6 mouse treated with 1 mg / kg / day myriocin (ISP-1) for 14 days. Fig. : Weight loss with increasing concentration (mg / kg / day) of myriocin (ISP-1) in mice with acid sphingomyelinase deficiency (SMPD1 KO), an animal model of human Niemann-Pick disease type A and B. Fig. : Weight loss with increasing concentration (mg / kg / day) of myriocin (ISP-1) in C57BL / 6 wild-type mice additionally fed 50% sugar water. Fig. : Weight loss with increasing concentration (mg / kg / day) of myriocin (ISP-1) in mice with acid sphingomyelinase (SMPD1) deficiency, an animal model of human Niemann-Pick disease type A and B, which were additionally fed 50% sugar water. Fig. : Feed intake of the animals under the different conditions described above. Fig. : Drinking water intake when given 50% sugar water compared to normal water without additives. Fig. Lipid profiles in the large intestine, small intestine and microbiome samples from untreated and C57BL / 6 wild-type mice treated with 0.3 mg / kg / day myriocin. Fig. : Lipid profiles in the large intestine, small intestine and microbiome samples from untreated and treated mice with 0.3 and 1 mg / kg / day myriocin with acid sphingomyelinase deficiency (SMPD1 ko), an animal model of human Niemann-Pick disease type A and B. Terms used

[0011] The term "obesity" is used synonymously with "morbid obesity," "adiposity," and "obesitas" in this context and refers to a nutritional and metabolic disease characterized by severe overweight and a positive energy balance, marked by an excessive accumulation of body fat. According to the WHO definition, obesity is present in individuals with a body mass index (BMI) of 30 kg / m² or higher. 2 before. Three severity levels are distinguished based on BMI: - Obesity grade I: BMI 30 - 34.9; - Obesity grade II: BMI 35 - 39.9; - Obesity grade III: BMI ≥40

[0012] The body mass index is expressed as BMI = mL -2 calculated, where m denotes the patient's body mass in kg and L the body length in m. Detailed description of the invention

[0013] According to a first aspect, the invention relates to a pharmaceutical composition prepared for oral administration for the treatment of obesity. The pharmaceutical composition according to the invention comprises an active ingredient which inhibits serine palmitoyltransferase (EC 2.1.3.50).

[0014] In preferred embodiments, the active ingredient contained in the pharmaceutical composition according to the invention comprises myriocin.

[0015] In particularly preferred embodiments, a dose unit of the pharmaceutical composition according to the invention comprises 10 to 30 mg of active ingredient.

[0016] Analogous to the optimal dose of 0.3 to 1 mg / kg per day found in mice, the dose for administration in an 80 kg person is 25-80 mg per day.

[0017] Another aspect of the invention relates to the use of myriocin for the treatment of obesity.

[0018] In preferred embodiments, the myriocin is administered orally.

[0019] In particularly preferred embodiments, the myriocin is administered at a dose of 50 to 150 mg per day, in particular at a dose of 30-90 mg per day.

[0020] The invention described here encompasses the following aspects: 1.) The oral use of SPT inhibitors, especially myriocin, for dose-dependent weight reduction with few side effects. 2.) The use of SPT inhibitors, including myriocin, regardless of nutritional and disease status.

[0021] The accumulation of SPT inhibitors, including myriocin, in the gut and microbiome appears to be an important aspect of the underlying mechanism of action.

[0022] The invention demonstrates for the first time a dose-dependent weight loss in mice treated with the SPT inhibitor myriocin ( Fig. The effect occurred immediately and continued in a dose-dependent manner over the 14-day treatment period. The results of this experiment thus demonstrate for the first time a dose-dependent effect of treatment with SPT inhibitors, using myriocin as an example, on weight loss in mammals, specifically mice.

[0023] Without wanting to be bound by their hypotheses, the inventors suspect that the reason for the weight-reducing effect of SPT inhibitors such as myriocin is the organ-specific accumulation of the substance in the intestine ( Fig. ) and in the microbiome ( Fig. ). The observed accumulation of myriocin in the gut and microbiome was only observed with oral administration of myriocin, but not with intraperitoneal (IP) administration. While IP administration revealed small detectable amounts of myriocin even in internal organs such as the liver and spleen, myriocin could not be detected in internal organs beyond the gut after oral administration ( Fig. ). This specific accumulation of myriocin in the gut and microbiome after oral administration was crucial for the weight-reducing effect, as intraperitoneal administration of myriocin did not cause progressive weight loss in mice ( Fig. The invention thus encompasses all SPT inhibitors that, like orally administered myriocin, accumulate in the intestine and the microbiome after application and can thereby induce progressive dose-dependent weight loss.

[0024] Since current literature suggests that SPT deficiency in intestinal bacteria can lead to an inflammatory response in the gut, mice were examined for possible intestinal inflammation after oral treatment with 1 mg / kg / day of myriocin for 14 days. The results of this examination showed no signs of intestinal inflammation. Fig. ).

[0025] To determine whether the invention also has an effect in cases of pre-existing metabolic disorders, mice with acid sphingomyelinase deficiency (SMPD1 ko) were treated orally with increasing concentrations of myriocin for 14 days. SMPD1 ko mice serve as an animal model for Niemann-Pick disease (NPD) types A and B. NPD is a lysosomal lipid storage disease with a pronounced neurodegenerative phenotype. Treatment with myriocin showed the same effect in the SMPD1 ko mice as in normal wild-type mice, so that the invention led to weight reduction regardless of the pathological background. Fig. Weight loss could still be induced when the animals were fed 50% (g / v) sugar water in addition to their normal diet ( Fig. ). The combination of 50% (g / v) sugar water and the genetic background of SMPD1 deficiency also had no effect on the dose-dependent efficacy of myriocin ( Fig. This finding clearly shows that weight loss through treatment with SPT inhibitors was independent of both pre-existing conditions and diet. The invention thus also works in pathologically altered underlying conditions and with different diets. Determining the food intake of the mice in the individual experiments showed that neither SMPD1 deficiency nor oral treatment with myriocin led to a change in the amount of food consumed ( Fig. Treatment with 50% (g / v) sugar water alone resulted in a 50% reduction in solid food intake, while simultaneously increasing sugar water consumption by 75%. Fig. The analysis of food consumption therefore impressively demonstrates that when sugar water was offered, more liquid food and less solid food was consumed. Despite this significantly altered food intake, the weight-reducing effect of oral myriocin treatment was maintained.

[0026] The effect of myriocin is primarily due to the reduced absorption of lipids, resulting from its specific accumulation in the intestine. This was also clearly demonstrated by the determination of lipid profiles ( Fig. In contrast to intestinal tissues, microbiome samples showed the greatest differences in all lipid classes (sphingosines, sphingomyelins, phosphatidylcholines, and lysophosphatidylcholines). These differences were characterized by an increase in the concentration of individual lipids following treatment with myriocin (ISP-1). The only significant decrease in concentration observed in the microbiome during treatment was 3-ketosphinganine, the direct product of SPT. This decrease highlights the inhibitory effect of myriocin (ISP-1) on SPT and demonstrates the preferential inhibitory activity of the administered amount of myriocin (ISP-1) in the microbiome.

[0027] In summary, the gut- and microbiome-specific accumulation of SPT inhibitors leads to a change in lipid metabolism, primarily within the microbiome. Presumably, when SPT is endogenously inhibited and the de novo synthesis of the gut bacteria is disrupted, they increasingly take up lipids from their environment, which are then no longer available to the host. This would explain the accumulation of various lipids in the microbiome of mice treated with myriocin (ISP-1). The reduced intestinal absorption of lipids then leads to the observed weight loss. The gut- and microbiome-specific application of SPT inhibitors, achieved, among other methods, through oral administration of myriocin (ISP-1), can therefore be used as a novel method for weight reduction.Animal studies show that myriocin (ISP-1), when administered orally, preferentially accumulates in the microbiome, and its poor bioavailability in other peripheral tissues largely avoids side effects in other organ systems. Analysis of the intestine showed no signs of intestinal inflammation. Weight reduction was evident even when supplemented with 50% sugar water and in SMPD1-deficient mice, indicating that the effect is maintained even in cases of malnutrition and underlying metabolic disorders.

[0028] An important aspect of the invention can be seen in the fact that the dose-dependent specific inhibition of SPT in the intestine and in the microbiome can trigger a weight reduction in the host.

[0029] These are (a) Inhibitors of SPT such as myriocin (ISP-1), which (b) preferentially accumulate in the gut and the microbiome and (c) influence metabolism there independently of pre-existing conditions and diets.

[0030] Key features of the invention are: 1. The effect is dose-dependent. 2. The treatment is administered orally and is non-invasive. 3. The invention has few side effects due to poor bioavailability. 4. The invention works independently of metabolic disorders. 5. The invention works independently of the diet. 6. The site of action is primarily located in the gut and the microbiome. 7. The effect is transient and reversible through exchange of the microbiome (stool). 8. The invention could significantly reduce obesity as a disease of civilization and overweight as a risk factor for numerous diseases.

[0031] The invention can also be formulated as a method for treating a patient suffering from obesity by administering an effective amount of an active substance to the patient which is an inhibitor of SPT, in particular myriocin (ISP-1).

[0032] The invention can further be formulated as a method for producing a pharmaceutical formulation for treating a patient suffering from obesity, wherein an effective amount of an inhibitor of SPT is used as the active ingredient, in particular myriocin (ISP-1). Example 1: Oral treatment of mice with myriocin

[0033] C57BL / 6 wild-type mice and SMPD1-deficient mice were kept under specific pathogen-free (SPF) conditions with standard food and drinking water ad libitum. Treated mice were given either 1.8 mg or 6.0 mg of myriocin added to 1 kg of standard food under sterile conditions to achieve an average daily dose of 0.3 mg / kg body weight and 1.0 mg / kg body weight, respectively. Sucrose (50% w / v) was dissolved in drinking water where specified. Food and water intake were determined by backweighing the food and water bottles. Mice were weighed regularly for weight determination. Example 2: Intraperitoneal (ip) injection of myriocin into mice

[0034] ApoE-deficient mice were kept under specific pathogen-free (SPF) conditions on a high-fat Western diet with ad libitum access to drinking water. Treated mice were administered daily under sterile conditions an isotonic saline solution containing 50 µg / mL of myriocin, the dosage of which was adjusted according to the mice's weight to achieve an average daily dose of 0.3 mg / kg body weight, e.g., 150 µL for a 25 g mouse. The mice were weighed regularly to determine their weight. Example 3: Assessment of colitis in mice

[0035] The colons were dissected, fixed in 4% formalin, embedded in paraffin, and sectioned into 4-µm sections. The deparaffinized sections were stained with hematoxylin and eosin (H&E). A 1 cm section of colon tissue was taken from the distal third of the colon and used for histological analysis. Three sections spaced 100 mm apart were evaluated. The mice were assessed individually, with each assessment representing the mean of three sections. The histological examination was performed by an independent reviewer who was blinded to the treatment. Histology was evaluated as follows: Epithelium (E) 0: normal morphology; 1: loss of goblet cells; 2: loss of goblet cells in large areas; 3: loss of crypts; 4: loss of crypts in large areas. Infiltration (I) 0: no infiltrate; 1: infiltrate around the crypt base; 2: infiltrate extending to the lumbar duct.3: extensive infiltration extending to the muscularis mucosae; 4: infiltration of the submucosa. The total histological score is the sum of the epithelial and infiltration scores and thus ranges from 0 to 8 (total score = E + I). In addition, the number of lymphoid follicles was counted in each section. Section lengths vary, and the number of lymphoid follicles counted is expressed as count / cm². An increased number of lymphoid follicles counted in histological sections may not be due to a de novo generation but rather to more frequent hits in the section due to the larger size. Example 4: Sample preparation for mass spectrometry

[0036] A weighted aliquot of approximately 50 mg of each tissue (spleen, liver, feces, small intestine, large intestine) was milled. After adding 1 mL of methanol and 10 µL of internal standard mixture (Table 1) as a reference for normalization and quantification, the samples were vigorously shaken in glass centrifuge tubes for 10 min and stored overnight at -80°C for protein precipitation. Subsequently, the samples were centrifuged at 1900 rpm for 5 min at 4°C. The clear supernatant was transferred to a new glass centrifuge tube, and the methanol was evaporated in a rotary vacuum concentrator. The dried sample was resuspended in 100 µL of methanol and transferred to a sampler tube with a microinsert for mass spectrometric analysis. Example 5: Determination of the concentration of myriocin and lipids

[0037] Quantifications were performed by high-performance liquid chromatography (HPLC) coupled with triple quadrupole mass spectrometry (LC-MS / MS). The Prominence HPLC system, consisting of the CBM-20A controller, the SIL-20AC automatic sampler, the CTO-20A column oven, the LC-20AD pump, and the LC-20A5R degasser (Shimadzu, Duisburg, Germany), was used for analyte separation. Ten µL of sample was injected onto a MultoHigh 100 RP18-3 60x2 mm column (CS Chromatographie Service GmbH, Langerwehe, Germany) at 35 °C under the specified conditions (Table 2). Mass spectrometric detection was performed using the QTrap triple quadrupole mass spectrometer in multiple reaction monitoring (MRM) mode with positive ionization at 450 °C (AB Sciex, Darmstadt, Germany). The detected mass transitions are listed (Table 3). The program Analyst 1.6 was used for the analysis based on internal standards (Table 1).3 used (AB Sciex). Table 1: Composition of the internal standard Analyt Endkonzentration Übergang (m / z) C17-Sphingosin (Sph) 3 µM 286 / 268 C17-Lysophosphatidylcholin (LPC) 3 µM 510 / 184 C17-Phosphatidylcholin (PC) 3 µM 762 / 184 C17-Sphingomyelin (SM) 3 µM 717 / 184 C17-Sphingosin-1-phosphat (S1P) 1 µM 366 / 250 Table 2: Chromatographic running conditions Zeit (min) Fluss (µL) Methanol (%) 1 % Ameisensäure in H2O 0.0 400 10 90 0.01 400 100 0 3.0 400 100 0 5.0 800 100 0 7.0 800 100 0 7.01 800 10 90 7.8 800 10 90 8.3 300 10 90 9.5 300 10 90 9.51 400 10 90 10.5 400 10 90 Table 3: List of analytes with corresponding internal standards and mass spectrometric transitions (m / z parent mass / target ion) Name Interner Standard Übergang (m / z) d18:1 So C17-Sphingosin (Sph) 300 / 282 d18:0 Sa C17-Sphingosin (Sph) 302 / 284 d18:1 So1P C17-Sphingosin-1-phosphat (S1P) 380 / 264 d18:0 Sa1P C17-Sphingosin-1-phosphat (S1P) 382 / 266 Deoxy_SA C17-Sphingosin (Sph) 286 / 268 Deoxy_Sph C17-Sphingosin (Sph) 284 / 266 Myriocin C17-Sphingosin (Sph) 402 / 104 SPC C17-Sphingosin (Sph) 465 / 184 SM (14:0) C17-Sphingomyelin (SM) 675.5 / 184 SM (16:0) C17-Sphingomyelin (SM) 703.5 / 184 SM (18:1) C17-Sphingomyelin (SM) 729.5 / 184 SM (18:0) C17-Sphingomyelin (SM) 731.5 / 184 SM (20:0) C17-Sphingomyelin (SM) 759.5 / 184 SM (22:0) C17-Sphingomyelin (SM) 797.5 / 184 SM (24:1) C17-Sphingomyelin (SM) 813.5 / 184 SM (24:0) C17-Sphingomyelin (SM) 815.5 / 184 PC (28:0) C17-Phosphatidylcholin (PC) 678.5 / 184 PC (30:0) C17-Phosphatidylcholin (PC) 706.5 / 184. PC (30:1) C17-Phosphatidylcholin (PC) 704.5 / 184 PC (32:0) C17-Phosphatidylcholin (PC) 734.5 / 184 PC (32:1) C17-Phosphatidylcholin (PC) 732.5 / 184 PC (34:0) C17-Phosphatidylcholin (PC) 762.5 / 184 PC (34:1) C17-Phosphatidylcholin (PC) 760.5 / 184 PC (34:2) C17-Phosphatidylcholin (PC) 758.5 / 184 PC (36:1) C17-Phosphatidylcholin (PC) 788.5 / 184 PC (36:2) C17-Phosphatidylcholin (PC) 786.5 / 184 LPC (16:0) C17-Lysophosphatidylcholin (LPC) 496 / 184 LPC (16:1) C17-Lysophosphatidylcholin (LPC) 494 / 184 LPC (18:0) C17-Lysophosphatidylcholin (LPC) 524 / 184 LPC (18:1) C17-Lysophosphatidylcholin (LPC) 522 / 184 LPC (18:2) C17-Lysophosphatidylcholin (LPC) 520 / 184 LPC (20:0) C17-Lysophosphatidylcholin (LPC) 552 / 184 Name Interner Standard Übergang (m / z) LPC (20:1) C17-Lysophosphatidylcholin (LPC) 550 / 184 LPC (20:3) C17-Lysophosphatidylcholin (LPC) 546 / 184 LPC (20:4) C17-Lysophosphatidylcholin (LPC) 544 / 184 Lyso-PAF C17-Lysophosphatidylcholin (LPC) 842 / 104 3-keto-SA C17-Sphingosin (Sph) 300 / 270 Publications cited: 1. 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Cell Chem Biol, 2020. 27(5): p. 586-597 e12 DOI: 10.1016 / j.chembiol.2020.03.008. 15. De Vita, T., C. Albani, N. Realini, M. Migliore, A. Basit, G. Ottonello, and A. Cavalli, Inhibition of Serine Palmitoyltransferase by a Small Organic Molecule Promotes Neuronal Survival after Astrocyte Amyloid Beta 1-42 Injury. ACS Chem Neurosci, 2019. 10(3): p. 1627-1635 DOI: 10.1021 / acschemneuro.8b00556. 16. Genin, MJ, IC Gonzalez Valcarcel, WG Holloway, J Lamar, M Mosior, E Hawkins, T Estridge, J Weidner, T Seng, D Yurek, LA Adams, J Weller, VL Reynolds, and JT Brozinick, Imidazopyridine and Pyrazolopiperidine Derivatives as Novel Inhibitors of Serine Palmitoyl Transferase. J Med Chem, 2016. 59(12): p. 5904-10 DOI: 10.1021 / acs.jmedchem.5b01851. QUOTES INCLUDED IN THE DESCRIPTION

[0000] This list of documents cited by the applicant was automatically generated and is included solely for the reader's convenience. The list is not part of the German patent or utility model application. The DPMA accepts no liability for any errors or omissions. Cited non-patent literature

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[0007] Brown, EM, X. Ke, D. Hitchcock, S. Jeanfavre, J. Avila-Pacheco, T. Nakata, TD Arthur, N. Fornelos, C. Heim, C. Franzosa, N. Watson, C. Huttenhower, HJ Haiser, G. Dillow, DB Graham, BB Finlay, AD Kostic, JA Porter, H. Vlamakis, CB Clish, RJ Xavier, Bacteroides-Derived Sphingolipids Are Critical for Maintaining Intestinal Homeostasis and Symbiosis. Cell Host Microbe, 2019. 25(5): p. 668–680 e7 DOI: 10.1016 / j.chom.2019.04.002

[0037] Kojima , T. , Y. Asano , O. Kurasawa , Y. Hirata , N. Iwamura , TT Wong , B. Saito , Y. Tanaka , R. Arai , K. Yonemori , Y. Miyamoto , Y. Sagiya , M. Yaguchi , S. Shibata , A. Mizutani , O. Sano , R. Adachi , Y. Satomi , M. Hirayama Aoyama, Y. Hiura, A. Kiba, S. Kitamura, and S. Imamura, Discovery of novel serine palmitoyltransferase inhibitors as cancer therapeutic agents. Bioorg Med Chem, 2018. 26(9): p. 2452–2465 DOI: 10.1016 / j.bmc.2018.04.008

[0037] . Horn, W.S., J.L. Smith, G.F. Bills, S.L. Raghoobar, G.L. Helms, M.B. Kurtz, J.A. Marrinan, B.R. Frommer, R.A. Thornton, and S.M. Mandala, Sphingofungins E and F: novel serinepalmitoyl transferase inhibitors from Paecilomyces variotii. J Antibiot (Tokyo), 1992. 45(10): p. 1692-6 DOI: 10.7164 / antibiotics.45.1692

[0037] Zweerink, M.M., A.M. Edison, G.B. Wells, W. Pinto, and R.L. Lester, Characterization of a novel, potent, and specific inhibitor of serine palmitoyltransferase. J Biol Chem, 1992. 267(35): p. 25032-8

[0037] Mandala, S.M., B.R. Frommer, R.A. Thornton, M.B. Kurtz, N.M. Young, M.A. Cabello, O. Genilloud, J.M. Liesch, J.L. Smith, and W.S. Horn, Inhibition of serine palmitoyl-transferase activity by lipoxamycin. J Antibiot (Tokyo), 1994. 47(3): p. 376-9 DOI: 10.7164 / antibiotics.47.376

[0037] Mandala, S.M. and G.H. Harris, Isolation and characterization of novelinhibitors of sphingolipid synthesis: australifungin, viridiofungins, rustmicin, and khafrefungin. Methods Enzymol, 2000. 311: p. 335-48 DOI: 10.1016 / s0076-6879(00)11094-8.

[0037] Mandala, S.M., R.A. Thornton, B.R. Frommer, S. Dreikorn, and M.B. Kurtz, Viridiofungins, novel inhibitors of sphingolipid synthesis. J Antibiot (Tokyo), 1997. 50(4): p. 339-43 DOI: 10.7164 / antibiotics.50.339

[0037] Yamaji-Hasegawa, A., A. Takahashi, Y. Tetsuka, Y. Senoh, and T. Kobayashi, Fungal metabolite sulfamisterin suppresses sphingolipid synthesis through inhibition of serine palmitoyltransferase. Biochemistry, 2005. 44(1): p. 268-77 DOI: 10.1021 / bi048605l

[0037] Sakamoto, H., K. Okamoto, M. Aoki, H. Kato, A. Katsume, A. Ohta, T. Tsukuda, N. Shimma, Y. Aoki, M. Arisawa, M. Kohara, and M. Sudoh, Host sphingolipid biosynthesis as a target for hepatitis C virus therapy. Nat Chem Biol, 2005. 1(6): p. 333-7 DOI: 10.1038 / change742

[0037] Katsume, A., Y. Tokunaga, Y. Hirata, T. Munakata, M. Saito, H. Hayashi, K. Okamoto, Y. Ohmori, I. Kusanagi, S. Fujiwara, T. Tsukuda, Y. Aoki, K. Klumpp, K. Tsukiyama-Kohara, A. El-Gohary, M. Sudoh, and M. Kohara, A serine Palmitoyltransferase inhibitor blocks hepatitis C virus replication in human hepatocytes. Gastroenterology, 2013. 145(4): p. 865-73 DOI: 10.1053 / j.gastro.2013.06.012

[0037] http: / / dx.doi.org / 10.1037 / 0033-295X.111.2.111 Ikushiro, H., H. Hayashi, and H. Kagamiyama, Reactions of serine palmitoyltransferase with serine and molecular mechanisms of the actions of serine derivatives as inhibitors. Biochemistry, 2004. 43(4): p. 1082–92 DOI: 10.1021 / bi035706v

[0037] . Sundaram, K.S. and M. Lev, L-cycloserine inhibition of sphingolipid synthesis in the anaerobic bacterium Bacteroides levii. Biochem Biophys Res Commun, 1984. 119(2): p. 814-9 DOI: 10.1016 / s0006-291x(84)80323-x

[0037] Medlock, K.A. and A.H. Merrill, Jr., Inhibition of serine palmitoyltransferase in vitro and long-chain base biosynthesis in intact Chinese hamster ovary cells by betachloroalanine. Biochemistry, 1988. 27(18): p. 7079-84 DOI: 10.1021 / bi00418a061

[0037] Hoch, D.G., D. Abegg, J.T. Hannich, D. Pechalrieu, A. Shuster, B.G. Dwyer, C. Wang, X. Zhang, Q. You, H. Riezman, and A. Adibekian, Combined Omics Approach Identifies Gambogic Acid and Related Xanthones as Covalent Inhibitors of the Serine Palmitoyltransferase Complex. Cell Chem Biol, 2020. 27(5): p. 586-597 e12 DOI: 10.1016 / j.chembiol.2020.03.008

[0037] De Vita, T., C. Albani, N. Realini, M. Migliore, A. Basit, G. Ottonello, and A. Cavalli, Inhibition of Serine Palmitoyltransferase by a Small Organic Molecule Promotes Neuronal Survival after Astrocyte Amyloid Beta 1-42 Injury. ACS Chem Neurosci, 2019. 10(3): p. 1627-1635 DOI: 10.1021 / acschemneuro.8b00556

[0037] Genin, M.J., I.C. Gonzalez Valcarcel, W.G. Holloway, J. Lamar, M. Mosior, E. Hawkins, T. Estridge, J. Weidner, T. Seng, D. Yurek, L.A. Adams, J. Weller, V.L. Reynolds, and J.T. Brozinick, Imidazopyridine and Pyrazolopiperidine Derivatives as Novel Inhibitors of Serine Palmitoyl Transferase. J Med Chem, 2016. 59(12): p. 5904-10 DOI: 10.1021 / acs.jmedchem.5b01851

[0037]

Claims

[1] Pharmaceutical composition formulated for oral administration, comprising an active ingredient which inhibits serine palmitoyltransferase (EC 2.1.3.50) for the treatment of obesity. [2] Pharmaceutical composition for the treatment of obesity according to claim 1, characterized by that the active ingredient contains myriocin. [3] Pharmaceutical composition for the treatment of obesity according to claim 2, characterized by that one dosage unit contains 10 to 30 mg of active ingredient. [4] Myriocin for use in the treatment of obesity. [5] Myriocin for use according to claim 4, wherein the myriocin is administered orally. [6] Myriocin for use according to claim 4 or 5, wherein the myriocin is administered in a dose of 50 to 150 mg per day, in particular in a dose of 30-90 mg per day.

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