Research output: Contribution to journal › Article › peer-review
Free fatty acid receptor 1 (GPR40) agonists containing spirocyclic periphery inspired by LY2881835. / Krasavin, Mikhail; Lukin, Alexey; Bagnyukova, Dania; Zhurilo, Nikolay; Zahanich, Ihor; Zozulya, Sergey; Ihalainen, Jouni; Forsberg, Markus M.; Lehtonen, Marko; Rautio, Jarkko; Moore, Daniel; Tikhonova, Irina G.
In: Bioorganic and Medicinal Chemistry, Vol. 24, No. 21, 01.11.2016, p. 5481-5494.Research output: Contribution to journal › Article › peer-review
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TY - JOUR
T1 - Free fatty acid receptor 1 (GPR40) agonists containing spirocyclic periphery inspired by LY2881835
AU - Krasavin, Mikhail
AU - Lukin, Alexey
AU - Bagnyukova, Dania
AU - Zhurilo, Nikolay
AU - Zahanich, Ihor
AU - Zozulya, Sergey
AU - Ihalainen, Jouni
AU - Forsberg, Markus M.
AU - Lehtonen, Marko
AU - Rautio, Jarkko
AU - Moore, Daniel
AU - Tikhonova, Irina G.
PY - 2016/11/1
Y1 - 2016/11/1
N2 - The free fatty acid receptor 1 (FFA1), a G protein-coupled receptor (GPCR) naturally activated by long chain fatty acids is a novel target for the treatment of metabolic diseases. The basic amine spirocyclic periphery of Eli Lilly's drug candidate LY2881835 for treatment of type 2 diabetes mellitus (which reached phase I clinical trials) inspired a series of novel FFA1 agonists. These were designed to incorporate the 3-[4-(benzyloxy)phenyl]propanoic acid pharmacophore core decorated with a range of spirocyclic motifs. The latter were prepared via the Prins cyclization and subsequent modification of the 4-hydroxytetrahydropyran moiety in the Prins product. Here, we synthesize 19 compounds and test for FFA1 activity. Within this pilot set, a nanomolar potency (EC50 = 55 nM) was reached. Four lead compounds (EC50 range 55-410 nM) were characterized for aqueous solubility, metabolic stability, plasma protein binding and Caco-2 permeability. While some instability in the presence of mouse liver microsomes was noted, mouse pharmacokinetic profile of the compound having the best overall ADME properties was evaluated to reveal acceptable bioavailability (F= 10.3%) and plasma levels achieved on oral administration. (C) 2016 Elsevier Ltd. All rights reserved.
AB - The free fatty acid receptor 1 (FFA1), a G protein-coupled receptor (GPCR) naturally activated by long chain fatty acids is a novel target for the treatment of metabolic diseases. The basic amine spirocyclic periphery of Eli Lilly's drug candidate LY2881835 for treatment of type 2 diabetes mellitus (which reached phase I clinical trials) inspired a series of novel FFA1 agonists. These were designed to incorporate the 3-[4-(benzyloxy)phenyl]propanoic acid pharmacophore core decorated with a range of spirocyclic motifs. The latter were prepared via the Prins cyclization and subsequent modification of the 4-hydroxytetrahydropyran moiety in the Prins product. Here, we synthesize 19 compounds and test for FFA1 activity. Within this pilot set, a nanomolar potency (EC50 = 55 nM) was reached. Four lead compounds (EC50 range 55-410 nM) were characterized for aqueous solubility, metabolic stability, plasma protein binding and Caco-2 permeability. While some instability in the presence of mouse liver microsomes was noted, mouse pharmacokinetic profile of the compound having the best overall ADME properties was evaluated to reveal acceptable bioavailability (F= 10.3%) and plasma levels achieved on oral administration. (C) 2016 Elsevier Ltd. All rights reserved.
KW - GPCR
KW - GPR40
KW - Free fatty acid receptor 1
KW - FFA1 agonists
KW - Type 2 diabetes mellitus
KW - Prins reaction
KW - Spirocyclic motifs
KW - Metabolic stability
KW - INSULIN-SECRETION
KW - DRUG DISCOVERY
KW - PROTEIN
KW - TAK-875
KW - CYCLIZATION
KW - EFFICACY
KW - BINDING
KW - POTENT
KW - CELLS
U2 - http://dx.doi.org/10.1016/j.bmc.2016.09.004
DO - http://dx.doi.org/10.1016/j.bmc.2016.09.004
M3 - статья
VL - 24
SP - 5481
EP - 5494
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
SN - 0968-0896
IS - 21
ER -
ID: 9434847