Discovery of benzofuran propanoic acid GPR120 agonists: From uHTS hit to mechanism-based pharmacodynamic effects.
The transformation of an aryloxybutanoic acid ultra high-throughput screening (uHTS) hit into a potent and selective series of G-protein coupled receptor 120 (GPR120) agonists is reported. uHTS hit 1 demonstrated an excellent rodent pharmacokinetic profile and selectivity over the related fatty acid receptor GPR40, but only modest GPR120 potency. Optimization of the "left-hand" aryl group led to compound 6, which demonstrated a GPR120 mechanism-based pharmacodynamic effect in a mouse oral glucose tolerance test (oGTT). Further optimization gave rise to the benzofuran propanoic acid series (exemplified by compound 37), which demonstrated acute mechanism-based pharmacodynamic effects. The combination of in vivo efficacy and attractive rodent pharmacodynamic profiles suggests compounds generated from this series may afford attractive candidates for the treatment of Type 2 diabetes.
Merck & Co., Inc., Kenilworth, NJ, USA. Electronic address: matthew_lombardo@merck.com.
Matthew
M
Lombardo
Merck & Co., Inc., Kenilworth, NJ, USA.
Kate
K
Bender
Merck & Co., Inc., Kenilworth, NJ, USA.
Clare
C
London
Merck & Co., Inc., Kenilworth, NJ, USA.
Michael A
MA
Plotkin
Merck & Co., Inc., Kenilworth, NJ, USA.
Melissa
M
Kirkland
Merck & Co., Inc., Kenilworth, NJ, USA.
Joel
J
Mane
Merck & Co., Inc., Kenilworth, NJ, USA.
Michele
M
Pachanski
Merck & Co., Inc., Kenilworth, NJ, USA.
Wayne
W
Geissler
Merck & Co., Inc., Kenilworth, NJ, USA.
John
J
Cummings
Merck & Co., Inc., Kenilworth, NJ, USA.
Bahanu
B
Habulihaz
Merck & Co., Inc., Kenilworth, NJ, USA.
Taro E
TE
Akiyama
Merck & Co., Inc., Kenilworth, NJ, USA.
Jerry
J
Di Salvo
Merck & Co., Inc., Kenilworth, NJ, USA.
Maria
M
Madeira
Merck & Co., Inc., Kenilworth, NJ, USA.
Joanna
J
Pols
Merck & Co., Inc., Kenilworth, NJ, USA.
Mary Ann
MA
Powles
Merck & Co., Inc., Kenilworth, NJ, USA.
Michael F
MF
Finley
Merck & Co., Inc., Kenilworth, NJ, USA.
Eric
E
Johnson
Merck & Co., Inc., Kenilworth, NJ, USA.
Thomas
T
Roussel
Merck & Co., Inc., Kenilworth, NJ, USA.
Victor N
VN
Uebele
Merck & Co., Inc., Kenilworth, NJ, USA.
Alejandro
A
Crespo
Merck & Co., Inc., Kenilworth, NJ, USA.
Dennis
D
Leung
Merck & Co., Inc., Kenilworth, NJ, USA.
Candice
C
Alleyne
Merck & Co., Inc., Kenilworth, NJ, USA.
Dorina
D
Trusca
Merck & Co., Inc., Kenilworth, NJ, USA.
Ying
Y
Lei
Merck & Co., Inc., Kenilworth, NJ, USA.
Andrew D
AD
Howard
Merck & Co., Inc., Kenilworth, NJ, USA.
Feroze
F
Ujjainwalla
Merck & Co., Inc., Kenilworth, NJ, USA.
James R
JR
Tata
Merck & Co., Inc., Kenilworth, NJ, USA.
Christopher J
CJ
Sinz
D000818:Animals; D001572:Benzofurans / Q000097:blood / Q000737:chemistry* / Q000494:pharmacology*; D001786:Blood Glucose / Q000032:analysis / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D057166:High-Throughput Screening Assays; D006801:Humans; D007004:Hypoglycemic Agents / Q000097:blood / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D011422:Propionates / Q000097:blood / Q000737:chemistry* / Q000494:pharmacology*; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000378:metabolism
D001572:Benzofurans; D001786:Blood Glucose; C519853:FFAR4 protein, human; D007004:Hypoglycemic Agents; D011422:Propionates; D043562:Receptors, G-Protein-Coupled; C029658:propionic acid
Aryloxybutanoic acid; Benzofuran propanoic acid; FFAR4; GPR120; Type 2 diabetes; Ultra high-throughput screening