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. 2018 Jun 14;9(7):685-690.
doi: 10.1021/acsmedchemlett.8b00149. eCollection 2018 Jul 12.

Structure-Activity Relationship of Novel and Selective Biaryl-Chroman GPR40 AgoPAMs

Helen Y Chen  1 , Christopher W Plummer  1 , Dong Xiao  1 , Harry R Chobanian  1 , Duane DeMong  1 , Michael Miller  1 , Maria E Trujillo  1 , Melissa Kirkland  1 , Daniel Kosinski  1 , Joel Mane  1 , Michele Pachanski  1 , Boonlert Cheewatrakoolpong  1 , Jerry Di Salvo  1 , Brande Thomas-Fowlkes  1 , Sarah Souza  1 , Daniel A Tatosian  1 , Qing Chen  1 , Michael J Hafey  1 , Robert Houle  1 , Andrew F Nolting  1 , Robert Orr  1 , Juliann Ehrhart  1 , Adam B Weinglass  1 , Richard Tschirret-Guth  1 , Andrew D Howard  1 , Steven L Colletti  1
Affiliations

Structure-Activity Relationship of Novel and Selective Biaryl-Chroman GPR40 AgoPAMs

Helen Y Chen et al. ACS Med Chem Lett. .

Abstract

A series of biaryl chromans exhibiting potent and selective agonism for the GPR40 receptor with positive allosteric modulation of endogenous ligands (AgoPAM) were discovered as potential therapeutics for the treatment of type II diabetes. Optimization of physicochemical properties through modification of the pendant aryl rings resulted in the identification of compound AP5, which possesses an improved metabolic profile while demonstrating sustained glucose lowering.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
GPR40 AgoPAM structural leads.
Scheme 1
Scheme 1. Library Synthesis for B-Ring Modifications
Reagents and conditions: (a) R-B(OH)2, 2 M K2CO3, Pd(dtbpf)Cl2, dioxane, 90 °C, 3 h; (b) 1 N NaOH, MeOH, rt, 3 h (8–44% yield over 2 steps).
Scheme 2
Scheme 2. Achiral Synthesis of 28 and 29 Using HDA
Reagents and conditions: (a) xylenes, 170 °C, 50 min, 41%; (b) 1 M aqueous LiOH, MeOH/THF, 65 °C, 19 h, 89%; (c) SFC separation: Chiral-pak AD-H (50 × 250 mm; 65% MeOH/CO2, 67%; (d) 1 M aqueous NaOH, MeCN/H2O, 95%.
Scheme 3
Scheme 3. Stereoselective Synthesis of AP5
Reagents and conditions: (a) t-BuX-Phos Palladacycle, Cy2NMe, toluene, 90 °C, 18 h, 49%; (b) formic acid, NEt3, RuCl[(R,R)-Tsdpen](Mesitylene), EtOAc, 22 h, quant.; (c) tBu3P, DIAD, THF, 1 h, 94%; purity upgrade by SFC, 74%; (d) 1 M aqueous LiOH, MeOH/THF, 55–58 °C, 17 h, 96%; (e) 1 M aqueous NaOH, MeCN/H2O, 95%.
Figure 2
Figure 2
GK rat oGTT titrations for AP5 and 29.
Figure 3
Figure 3
Dose-dependent GLP-1 secretion with AP5.
See this image and copyright information in PMC

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