title: Effects of pyrazole partial agonists on HCA(2) -mediated flushing and VLDL-triglyceride levels in mice.
abstract: OBJECTIVE
  Niacin can effectively treat dyslipidaemic disorders. However, its clinical use is limited due to the cutaneous flushing mediated by the nicotinic acid receptor HCA(2) . In the current study, we evaluated two partial agonists for HCA(2) , LUF6281 and LUF6283, with respect to their anti-dyslipidaemic potential and cutaneous flushing effect.
  
  
  METHODS
  In vitro potency and efficacy studies with niacin and the two HCA(2) partial agonists were performed using HEK293T cells stably expressing human HCA(2) . Normolipidaemic C57BL/6 mice received either niacin or the HCA(2) partial agonists (400 mg·kg(-1) ·day(-1) ) once a day for 4 weeks for evaluation of their effects in vivo.
  
  
  RESULTS
  Radioligand competitive binding assay showed K(i) values for LUF6281 and LUF6283 of 3 and 0.55 µM. [(35) S]-GTPγS binding revealed the rank order of their potency as niacin > LUF6283 > LUF6281. All three compounds reduced plasma VLDL-triglyceride concentrations similarly, while LUF6281 and LUF6283, in contrast to niacin, did not also exhibit the unwanted flushing side effect in C57BL/6 mice. Niacin reduced the expression of lipolytic genes HSL and ATGL in adipose tissue by 50%, whereas LUF6281 and LUF6283 unexpectedly did not. In contrast, the decrease in VLDL-triglyceride concentration induced by LUF6281 and LUF6283 was associated with a parallel >40% reduced expression of APOB within the liver.
  
  
  CONCLUSIONS
  The current study identifies LUF6281 and LUF6283, two HCA(2) partial agonists of the pyrazole class, as promising drug candidates to achieve the beneficial lipid lowering effect of niacin without producing the unwanted flushing side effect.
authors.affiliation: Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Leiden, The Netherlands.
authors.forename: Zhaosha
authors.initials: Z
authors.lastname: Li
authors.forename: Clara C
authors.initials: CC
authors.lastname: Blad
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: van der Sluis
authors.forename: Henk
authors.initials: H
authors.lastname: de Vries
authors.forename: Theo J C
authors.initials: TJ
authors.lastname: Van Berkel
authors.forename: Adriaan P
authors.initials: AP
authors.lastname: Ijzerman
authors.forename: Menno
authors.initials: M
authors.lastname: Hoekstra
mesh_terms: D000818:Animals; D005260:Female; D005483:Flushing / Q000139:chemically induced / Q000503:physiopathology; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D008079:Lipoproteins, VLDL / Q000097:blood*; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009525:Niacin / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology*; D011869:Radioligand Assay; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000502:physiology; D011978:Receptors, Nicotinic / Q000502:physiology; D012881:Skin Temperature / Q000187:drug effects; D014280:Triglycerides / Q000097:blood*
chemical_list: C530636:HCAR2 protein, human; D000960:Hypolipidemic Agents; C578191:LUF6281; C578192:LUF6283; D008079:Lipoproteins, VLDL; D011720:Pyrazoles; D043562:Receptors, G-Protein-Coupled; D011978:Receptors, Nicotinic; D014280:Triglycerides; C030106:very low density lipoprotein triglyceride; D009525:Niacin; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3