Tetrahydropyrazolo[4,3-c]pyridine derivatives as potent and peripherally selective cannabinoid-1 (CB1) receptor inverse agonists.
Peripherally restricted CB1 receptor inverse agonists hold potential as useful therapeutics to treat obesity and related metabolic diseases without causing undesired CNS-mediated adverse effects. We identified a series of tetrahydropyrazolo[4,3-c]pyridine derivatives as potent and highly peripherally selective CB1 receptor inverse agonists. This discovery was achieved by introducing polar functional groups into the molecule, which increase the topological polar surface area and reduce its brain-penetrating ability.
Janssen Research & Development, L.L.C., Welsh & McKean Roads, Spring House, PA 19477, USA(†).
Bin
B
Zhu
Janssen Research & Development, L.L.C., Welsh & McKean Roads, Spring House, PA 19477, USA(†).
Jay M
JM
Matthews
Janssen Research & Development, L.L.C., Welsh & McKean Roads, Spring House, PA 19477, USA(†).
Mingde
M
Xia
Janssen Research & Development, L.L.C., Welsh & McKean Roads, Spring House, PA 19477, USA(†).
Shawn
S
Black
Janssen Research & Development, L.L.C., Welsh & McKean Roads, Spring House, PA 19477, USA(†).
Cailin
C
Chen
Janssen Research & Development, L.L.C., Welsh & McKean Roads, Spring House, PA 19477, USA(†).
Cuifen
C
Hou
Janssen Research & Development, L.L.C., Welsh & McKean Roads, Spring House, PA 19477, USA(†).
Yin
Y
Liang
Janssen Research & Development, L.L.C., Welsh & McKean Roads, Spring House, PA 19477, USA(†).
Yuting
Y
Tang
Janssen Research & Development, L.L.C., Welsh & McKean Roads, Spring House, PA 19477, USA(†).
Mark J
MJ
Macielag
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D063387:Cannabinoid Receptor Antagonists / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D054314:Drug Inverse Agonism; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000188:drug therapy / Q000378:metabolism; D011720:Pyrazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D011725:Pyridines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D014018:Tissue Distribution
D063387:Cannabinoid Receptor Antagonists; D011720:Pyrazoles; D011725:Pyridines; D043884:Receptor, Cannabinoid, CB1
CB1 receptor; Cannabinoid receptor; Inverse agonist; Peripheral selectivity; Peripherally restricted