title: Orally available selective melanocortin-4 receptor antagonists stimulate food intake and reduce cancer-induced cachexia in mice.
abstract: BACKGROUND
  Cachexia is among the most debilitating and life-threatening aspects of cancer. It represents a metabolic syndrome affecting essential functional circuits involved in the regulation of homeostasis, and includes anorexia, fat and muscle tissue wasting. The anorexigenic peptide alpha-MSH is believed to be crucially involved in the normal and pathologic regulation of food intake. It was speculated that blockade of its central physiological target, the melanocortin (MC)-4 receptor, might provide a promising anti-cachexia treatment strategy. This idea is supported by the fact that in animal studies, agouti-related protein (AgRP), the endogenous inverse agonist at the MC-4 receptor, was found to affect two hallmark features of cachexia, i.e. to increase food intake and to reduce energy expenditure.
  
  
  RESULTS
  SNT207707 and SNT209858 are two recently discovered, non peptidic, chemically unrelated, orally active MC-4 receptor antagonists penetrating the blood brain barrier. Both compounds were found to distinctly increase food intake in healthy mice. Moreover, in mice subcutaneously implanted with C26 adenocarcinoma cells, repeated oral administration (starting the day after tumor implantation) of each of the two compounds almost completely prevented tumor induced weight loss, and diminished loss of lean body mass and fat mass.
  
  
  CONCLUSIONS
  In contrast to the previously reported peptidic and small molecule MC-4 antagonists, the compounds described here work by the oral administration route. Orally active compounds might offer a considerable advantage for the treatment of cachexia patients.
authors.affiliation: Santhera Pharmaceuticals (Switzerland) Ltd, Liestal, Switzerland.
authors.forename: Philipp
authors.initials: P
authors.lastname: Weyermann
authors.forename: Robert
authors.initials: R
authors.lastname: Dallmann
authors.forename: Josef
authors.initials: J
authors.lastname: Magyar
authors.forename: Corinne
authors.initials: C
authors.lastname: Anklin
authors.forename: Martina
authors.initials: M
authors.lastname: Hufschmid
authors.forename: Judith
authors.initials: J
authors.lastname: Dubach-Powell
authors.forename: Isabelle
authors.initials: I
authors.lastname: Courdier-Fruh
authors.forename: Marco
authors.initials: M
authors.lastname: Henneböhle
authors.forename: Sonja
authors.initials: S
authors.lastname: Nordhoff
authors.forename: Cesare
authors.initials: C
authors.lastname: Mondadori
mesh_terms: D000818:Animals; D001835:Body Weight; D001923:Brain Chemistry; D002100:Cachexia / Q000188:drug therapy*; D045744:Cell Line, Tumor; D004435:Eating / Q000187:drug effects*; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D011897:Random Allocation; D044105:Receptor, Melanocortin, Type 4 / Q000037:antagonists & inhibitors*
chemical_list: D044105:Receptor, Melanocortin, Type 4