Identification of a novel GPR81-selective agonist that suppresses lipolysis in mice without cutaneous flushing.
GPR81, which exhibits a high degree of homology with GPR109a, has been recently identified as a lactate receptor. Similar to GPR109a, the activation of GPR81 by lactate suppresses lipolysis, suggesting that GPR81 may be a potential drug target for treating dyslipidemia. In addition, the fact that GPR81 is expressed only in adipocytes, whereas GPR109a is expressed in various tissues and cells, including Langerhans cells, which are considered responsible for flushing, indicates that targeting GPR81 could lead to the development of antidyslipidemia agents with a reduced risk of this side effect. However, the pharmacological role of GPR81 remains largely unclear, mainly because of the lack of potent and selective surrogate GPR81 agonists suitable for in vivo studies. In the present study, we showed that lactate-induced suppression of lipolysis in explants of white adipose tissue (WAT) depends on the presence of GPR81. We also performed high-throughput screening (HTS) and identified four novel chemical clusters as GPR81 agonists. Chemical optimization of aminothiazole derivatives led to the discovery of a lead compound with improved potency. The compound inhibited lipolysis in differentiated 3T3-L1 adipocytes. Finally, intraperitoneal administration of this compound suppressed lipolysis in mice at doses that did not cause cutaneous flushing. This is the first description of a 50nM GPR81 selective agonist with in vivo efficacy, without the side effect, i.e., flushing. These results suggest that GPR81 is an attractive drug target for treating dyslipidemia without the risk of flushing.
Biomolecular Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: taku.sakurai@takeda.com.
Taku
T
Sakurai
Takeda Cambridge, 418 Cambridge Science Park, CB4 OPA Cambridge, GB, United Kingdom.
Richard
R
Davenport
Takeda Cambridge, 418 Cambridge Science Park, CB4 OPA Cambridge, GB, United Kingdom.
Stuart
S
Stafford
Takeda Cambridge, 418 Cambridge Science Park, CB4 OPA Cambridge, GB, United Kingdom.
Johannes
J
Grosse
Biomolecular Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
Kazumasa
K
Ogawa
Takeda Cambridge, 418 Cambridge Science Park, CB4 OPA Cambridge, GB, United Kingdom.
Jennifer
J
Cameron
Takeda Cambridge, 418 Cambridge Science Park, CB4 OPA Cambridge, GB, United Kingdom.
Laura
L
Parton
Takeda Cambridge, 418 Cambridge Science Park, CB4 OPA Cambridge, GB, United Kingdom.
Andy
A
Sykes
Takeda Cambridge, 418 Cambridge Science Park, CB4 OPA Cambridge, GB, United Kingdom.
Stephen
S
Mack
Takeda Cambridge, 418 Cambridge Science Park, CB4 OPA Cambridge, GB, United Kingdom.
Sarah
S
Bousba
Takeda Cambridge, 418 Cambridge Science Park, CB4 OPA Cambridge, GB, United Kingdom.
Alka
A
Parmar
Takeda Cambridge, 418 Cambridge Science Park, CB4 OPA Cambridge, GB, United Kingdom.
David
D
Harrison
Takeda Cambridge, 418 Cambridge Science Park, CB4 OPA Cambridge, GB, United Kingdom.
Louise
L
Dickson
Takeda Cambridge, 418 Cambridge Science Park, CB4 OPA Cambridge, GB, United Kingdom.
Mathew
M
Leveridge
Biomolecular Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
Junji
J
Matsui
Takeda Cambridge, 418 Cambridge Science Park, CB4 OPA Cambridge, GB, United Kingdom.
Matt
M
Barnes
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism; D052436:Adipose Tissue, White / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D005483:Flushing / Q000517:prevention & control*; D057166:High-Throughput Screening Assays; D000960:Hypolipidemic Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D019344:Lactic Acid / Q000494:pharmacology; D008066:Lipolysis / Q000187:drug effects*; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D014162:Transfection
C533610:HCAR1 protein, human; C529424:Hcar1 protein, mouse; D000960:Hypolipidemic Agents; D043562:Receptors, G-Protein-Coupled; D013844:Thiazoles; D019344:Lactic Acid
Dyslipidemia; GPCR; GPR81; HTS; Lipolysis