Novel FFA1 (GPR40) agonists containing spirocyclic periphery: polar azine periphery as a driver of potency
A series of nine compounds based on 3-[4-(benzyloxy)phenyl]propanoic acid core containing a 1-oxa-9-azaspiro[5.5]undecane periphery was designed, synthesized and evaluated as free fatty acid 1 (FFA1 or GPR40) agonists. The spirocyclic appendages included in these compounds were inspired by LY2881835...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Taylor & Francis Group
2017-01-01
|
| Series: | Journal of Enzyme Inhibition and Medicinal Chemistry |
| Subjects: | |
| Online Access: | http://dx.doi.org/10.1080/14756366.2016.1230110 |
| _version_ | 1818041704105639936 |
|---|---|
| author | Mikhail Krasavin Alexey Lukin Daria Bagnyukova Nikolay Zhurilo Ihor Zahanich Sergey Zozulya |
| author_facet | Mikhail Krasavin Alexey Lukin Daria Bagnyukova Nikolay Zhurilo Ihor Zahanich Sergey Zozulya |
| author_sort | Mikhail Krasavin |
| collection | DOAJ |
| description | A series of nine compounds based on 3-[4-(benzyloxy)phenyl]propanoic acid core containing a 1-oxa-9-azaspiro[5.5]undecane periphery was designed, synthesized and evaluated as free fatty acid 1 (FFA1 or GPR40) agonists. The spirocyclic appendages included in these compounds were inspired by LY2881835, Eli Lilly’s advanced drug candidate for type II diabetes mellitus that was in phase I clinical trials. These polar spirocyclic, fully saturated appendages (that are themselves uncharacteristic of the known FFA1 ligand space) were further decorated with diverse polar groups (such as basic heterocycles or secondary amides). To our surprise, while seven of nine compounds were found to be inactive (likely due to the decrease in lipophilicity, which is known to be detrimental to FFA1 ligand affinity), two compounds containing 2-pyridyloxy and 2-pyrimidinyloxy groups were found to have EC50 of 1.621 and 0.904 µM, respectively. This result is significant in the context of the worldwide quest for more polar FFA1 agonists, which would be devoid of liver toxicity effects earlier observed for a FFA1 agonist fasiglifam (TAk-875) in clinical studies. |
| first_indexed | 2024-12-10T08:34:39Z |
| format | Article |
| id | doaj.art-5d8999bb7c674341b63a5e6d5a3ae0a5 |
| institution | Directory Open Access Journal |
| issn | 1475-6366 1475-6374 |
| language | English |
| last_indexed | 2024-12-10T08:34:39Z |
| publishDate | 2017-01-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Journal of Enzyme Inhibition and Medicinal Chemistry |
| spelling | doaj.art-5d8999bb7c674341b63a5e6d5a3ae0a52022-12-22T01:56:00ZengTaylor & Francis GroupJournal of Enzyme Inhibition and Medicinal Chemistry1475-63661475-63742017-01-01321293610.1080/14756366.2016.12301101230110Novel FFA1 (GPR40) agonists containing spirocyclic periphery: polar azine periphery as a driver of potencyMikhail Krasavin0Alexey Lukin1Daria Bagnyukova2Nikolay Zhurilo3Ihor Zahanich4Sergey Zozulya5Saint Petersburg State UniversityMoscow Technological UniversityMoscow Technological UniversityMoscow Technological UniversityEnamine Ltd.Enamine Ltd.A series of nine compounds based on 3-[4-(benzyloxy)phenyl]propanoic acid core containing a 1-oxa-9-azaspiro[5.5]undecane periphery was designed, synthesized and evaluated as free fatty acid 1 (FFA1 or GPR40) agonists. The spirocyclic appendages included in these compounds were inspired by LY2881835, Eli Lilly’s advanced drug candidate for type II diabetes mellitus that was in phase I clinical trials. These polar spirocyclic, fully saturated appendages (that are themselves uncharacteristic of the known FFA1 ligand space) were further decorated with diverse polar groups (such as basic heterocycles or secondary amides). To our surprise, while seven of nine compounds were found to be inactive (likely due to the decrease in lipophilicity, which is known to be detrimental to FFA1 ligand affinity), two compounds containing 2-pyridyloxy and 2-pyrimidinyloxy groups were found to have EC50 of 1.621 and 0.904 µM, respectively. This result is significant in the context of the worldwide quest for more polar FFA1 agonists, which would be devoid of liver toxicity effects earlier observed for a FFA1 agonist fasiglifam (TAk-875) in clinical studies.http://dx.doi.org/10.1080/14756366.2016.1230110AgonistscLogPfree fatty acid receptor 1GPR40potencytotal polar surface area |
| spellingShingle | Mikhail Krasavin Alexey Lukin Daria Bagnyukova Nikolay Zhurilo Ihor Zahanich Sergey Zozulya Novel FFA1 (GPR40) agonists containing spirocyclic periphery: polar azine periphery as a driver of potency Journal of Enzyme Inhibition and Medicinal Chemistry Agonists cLogP free fatty acid receptor 1 GPR40 potency total polar surface area |
| title | Novel FFA1 (GPR40) agonists containing spirocyclic periphery: polar azine periphery as a driver of potency |
| title_full | Novel FFA1 (GPR40) agonists containing spirocyclic periphery: polar azine periphery as a driver of potency |
| title_fullStr | Novel FFA1 (GPR40) agonists containing spirocyclic periphery: polar azine periphery as a driver of potency |
| title_full_unstemmed | Novel FFA1 (GPR40) agonists containing spirocyclic periphery: polar azine periphery as a driver of potency |
| title_short | Novel FFA1 (GPR40) agonists containing spirocyclic periphery: polar azine periphery as a driver of potency |
| title_sort | novel ffa1 gpr40 agonists containing spirocyclic periphery polar azine periphery as a driver of potency |
| topic | Agonists cLogP free fatty acid receptor 1 GPR40 potency total polar surface area |
| url | http://dx.doi.org/10.1080/14756366.2016.1230110 |
| work_keys_str_mv | AT mikhailkrasavin novelffa1gpr40agonistscontainingspirocyclicperipherypolarazineperipheryasadriverofpotency AT alexeylukin novelffa1gpr40agonistscontainingspirocyclicperipherypolarazineperipheryasadriverofpotency AT dariabagnyukova novelffa1gpr40agonistscontainingspirocyclicperipherypolarazineperipheryasadriverofpotency AT nikolayzhurilo novelffa1gpr40agonistscontainingspirocyclicperipherypolarazineperipheryasadriverofpotency AT ihorzahanich novelffa1gpr40agonistscontainingspirocyclicperipherypolarazineperipheryasadriverofpotency AT sergeyzozulya novelffa1gpr40agonistscontainingspirocyclicperipherypolarazineperipheryasadriverofpotency |