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. 2017 Jan 23;8(2):221-226.
doi: 10.1021/acsmedchemlett.6b00443. eCollection 2017 Feb 9.

Design and Synthesis of Novel, Selective GPR40 AgoPAMs

Christopher W Plummer  1 , Matthew J Clements  1 , Helen Chen  1 , Murali Rajagopalan  1 , Hubert Josien  1 , William K Hagmann  1 , Michael Miller  1 , Maria E Trujillo  1 , Melissa Kirkland  1 , Daniel Kosinski  1 , Joel Mane  1 , Michele Pachanski  1 , Boonlert Cheewatrakoolpong  1 , Andrew F Nolting  1 , Robert Orr  1 , Melodie Christensen  1 , Louis-Charles Campeau  1 , Michael J Wright  1 , Randal Bugianesi  1 , Sarah Souza  1 , Xiaoping Zhang  1 , Jerry Di Salvo  1 , Adam B Weinglass  1 , Richard Tschirret-Guth  1 , Ravi Nargund  1 , Andrew D Howard  1 , Steven L Colletti  1
Affiliations

Design and Synthesis of Novel, Selective GPR40 AgoPAMs

Christopher W Plummer et al. ACS Med Chem Lett. .

Abstract

GPR40 is a G-protein-coupled receptor expressed primarily in pancreatic islets and intestinal L-cells that has been a target of significant recent therapeutic interest for type II diabetes. Activation of GPR40 by partial agonists elicits insulin secretion only in the presence of elevated blood glucose levels, minimizing the risk of hypoglycemia. GPR40 agoPAMs have shown superior efficacy to partial agonists as assessed in a glucose tolerability test (GTT). Herein, we report the discovery and optimization of a series of potent, selective GPR40 agoPAMs. Compound 24 demonstrated sustained glucose lowering in a chronic study of Goto Kakizaki rats, showing no signs of tachyphylaxis for this mechanism.

Keywords: FFA1; GPCR; GPR40; agoPAM; chroman; diabetes; insulin secretogogue.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
GPR40 “full agonists” and partial agonists.
Figure 2
Figure 2
Medicinal chemistry tactics to identify GPR40 agoPAMs with improved ligand efficiency.
Figure 3
Figure 3
AgoPAMs deliver increased % activation in IP1 assay.
Scheme 1
Scheme 1
Reagents and conditions: (a) TBSCl, imidazole, DMF, 98%; (b) LDA, MeI, THF; then KOtBu, HCl; (c) TBAF, THF, 70% over 3 steps, 3:1 dr 36/35; (d) paraformaldehyde, MgCl2, TEA, MeCN, 74%; (e) NaBH4, MeOH, 95%; (f) Pd(PPh3)4, K2CO3, dioxane, 93%; (g) Montmorillonite K10, LiClO4, H2O, MeNO2, 36%; (h) LiOH, MeOH, H2O, THF, 60 °C, 96%; (i) SFC separation, AD-H chiralpak, 60% IPA/CO2 with 0.2% HN(iPr)2 modifier.
Scheme 2
Scheme 2
Reagents and conditions: (a) Cataxium-Pd precat, K3PO3, MeCN, 89%; (b) Ru-Josiphos, BF4H-Et2O, 500 atm H2, 85°, MeOH, 86%, 98% ee; (c) Pd/Pt/C, H2 gas, MeOH, 104%; (d) NIS, DCM, 91%; (e) Pd(PPh3)4, K2CO3, 1,4-dioxane, 98%; (f) vinylmagnesium bromide, THF, 67%; (g) tBuXPHOS Pd precat, MeN(Cy)2, PhMe, 68%; (h) RuCl[(R,R)-TsDPEN(mesitylene)], TEA, formic acid, MeCN, 100%, 92:8 dr; (i) PPh3, DIAD, DCM, 83%; (j) LiOH, THF/MeOH/water, 97%; (k) SFC separation conditions.
Figure 4
Figure 4
(A) IP1 functional assay [− or + human serum (HS)]. (B,C) [3H]L358 and [3H]25 binding assays.
Figure 5
Figure 5
GK Rat oGTT titrations.
Figure 6
Figure 6
GLP-1 secretion for GPR40 KO versus WT mice.
Figure 7
Figure 7
AgoPAM GK rat chronic study with 24.
See this image and copyright information in PMC

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