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Discovery of polar spirocyclic orally bioavailable urea inhibitors of soluble epoxide hydrolase. / Lukin, Alexey; Kramer, Jan; Hartmann, Markus; Weizel, Lilia; Hernandez-Olmos, Victor; Falahati, Konstantin; Burghardt, Irene; Kalinchenkova, Natalia; Bagnyukova, Darya; Zhurilo, Nikolay; Rautio, Jarkko; Forsberg, Markus; Ihalainen, Jouni; Auriola, Seppo; Leppänen, Jukka; Konstantinov, Igor; Pogoryelov, Denys; Proschak, Ewgenij; Dar'in, Dmitry; Krasavin, Mikhail.

In: Bioorganic Chemistry, Vol. 80, 01.10.2018, p. 655-667.

Research output: Contribution to journal › Article › peer-review

Harvard

Lukin, A, Kramer, J, Hartmann, M, Weizel, L, Hernandez-Olmos, V, Falahati, K, Burghardt, I, Kalinchenkova, N, Bagnyukova, D, Zhurilo, N, Rautio, J, Forsberg, M, Ihalainen, J, Auriola, S, Leppänen, J, Konstantinov, I, Pogoryelov, D, Proschak, E, Dar'in, D & Krasavin, M 2018, 'Discovery of polar spirocyclic orally bioavailable urea inhibitors of soluble epoxide hydrolase', Bioorganic Chemistry, vol. 80, pp. 655-667. https://doi.org/10.1016/j.bioorg.2018.07.014

APA

Lukin, A., Kramer, J., Hartmann, M., Weizel, L., Hernandez-Olmos, V., Falahati, K., Burghardt, I., Kalinchenkova, N., Bagnyukova, D., Zhurilo, N., Rautio, J., Forsberg, M., Ihalainen, J., Auriola, S., Leppänen, J., Konstantinov, I., Pogoryelov, D., Proschak, E., Dar'in, D., & Krasavin, M. (2018). Discovery of polar spirocyclic orally bioavailable urea inhibitors of soluble epoxide hydrolase. Bioorganic Chemistry, 80, 655-667. https://doi.org/10.1016/j.bioorg.2018.07.014

Vancouver

Lukin A, Kramer J, Hartmann M, Weizel L, Hernandez-Olmos V, Falahati K et al. Discovery of polar spirocyclic orally bioavailable urea inhibitors of soluble epoxide hydrolase. Bioorganic Chemistry. 2018 Oct 1;80:655-667. https://doi.org/10.1016/j.bioorg.2018.07.014

Author

Lukin, Alexey ; Kramer, Jan ; Hartmann, Markus ; Weizel, Lilia ; Hernandez-Olmos, Victor ; Falahati, Konstantin ; Burghardt, Irene ; Kalinchenkova, Natalia ; Bagnyukova, Darya ; Zhurilo, Nikolay ; Rautio, Jarkko ; Forsberg, Markus ; Ihalainen, Jouni ; Auriola, Seppo ; Leppänen, Jukka ; Konstantinov, Igor ; Pogoryelov, Denys ; Proschak, Ewgenij ; Dar'in, Dmitry ; Krasavin, Mikhail. / Discovery of polar spirocyclic orally bioavailable urea inhibitors of soluble epoxide hydrolase. In: Bioorganic Chemistry. 2018 ; Vol. 80. pp. 655-667.

BibTeX

@article{eaaff6255a864eb2a53ed9516e7db3a0,
title = "Discovery of polar spirocyclic orally bioavailable urea inhibitors of soluble epoxide hydrolase",
abstract = "Spirocyclic 1-oxa-9-azaspiro[5.5]undecan-4-amine scaffold was explored as a basis for the design of potential inhibitors of soluble epoxide hydrolase (sEH). Synthesis and testing of the initial SAR-probing library followed by biochemical testing against sEH allowed nominating a racemic lead compound (±)-22. The latter showed remarkable (> 0.5 mM) solubility in aqueous phosphate buffer solution, unusually low (for sEH inhibitors) lipophilicity as confirmed by experimentally determined logD7.4 of 0.99, and an excellent oral bioavailability in mice (as well as other pharmacokinetic characteristics). Individual enantiomer profiling revealed that the inhibitory potency primarily resided with the dextrorotatory eutomer (+)-22 (IC50 4.99 ± 0.18 nM). For the latter, a crystal structure of its complex with a C-terminal domain of sEH was obtained and resolved. These data fully validate (+)-22 as a new non-racemic advanced lead compound for further development as a potential therapeutic agent for use in such areas as cardiovascular disease, inflammation and pain.",
keywords = "1-Oxa-9-azaspiro[5.5]undecan-4-amine, Distomer, Eutomer, Low LogD, Oral bioavailability, Orthogonal periphery group variation, Phosphate buffer solubility, Prins reaction, Protein-ligand crystal structure, Spirocyclic",
author = "Alexey Lukin and Jan Kramer and Markus Hartmann and Lilia Weizel and Victor Hernandez-Olmos and Konstantin Falahati and Irene Burghardt and Natalia Kalinchenkova and Darya Bagnyukova and Nikolay Zhurilo and Jarkko Rautio and Markus Forsberg and Jouni Ihalainen and Seppo Auriola and Jukka Lepp{\"a}nen and Igor Konstantinov and Denys Pogoryelov and Ewgenij Proschak and Dmitry Dar'in and Mikhail Krasavin",
year = "2018",
month = oct,
day = "1",
doi = "10.1016/j.bioorg.2018.07.014",
language = "English",
volume = "80",
pages = "655--667",
journal = "Bioorganic Chemistry",
issn = "0045-2068",
publisher = "Elsevier",

}

RIS

TY - JOUR

T1 - Discovery of polar spirocyclic orally bioavailable urea inhibitors of soluble epoxide hydrolase

AU - Lukin, Alexey

AU - Kramer, Jan

AU - Hartmann, Markus

AU - Weizel, Lilia

AU - Hernandez-Olmos, Victor

AU - Falahati, Konstantin

AU - Burghardt, Irene

AU - Kalinchenkova, Natalia

AU - Bagnyukova, Darya

AU - Zhurilo, Nikolay

AU - Rautio, Jarkko

AU - Forsberg, Markus

AU - Ihalainen, Jouni

AU - Auriola, Seppo

AU - Leppänen, Jukka

AU - Konstantinov, Igor

AU - Pogoryelov, Denys

AU - Proschak, Ewgenij

AU - Dar'in, Dmitry

AU - Krasavin, Mikhail

PY - 2018/10/1

Y1 - 2018/10/1

N2 - Spirocyclic 1-oxa-9-azaspiro[5.5]undecan-4-amine scaffold was explored as a basis for the design of potential inhibitors of soluble epoxide hydrolase (sEH). Synthesis and testing of the initial SAR-probing library followed by biochemical testing against sEH allowed nominating a racemic lead compound (±)-22. The latter showed remarkable (> 0.5 mM) solubility in aqueous phosphate buffer solution, unusually low (for sEH inhibitors) lipophilicity as confirmed by experimentally determined logD7.4 of 0.99, and an excellent oral bioavailability in mice (as well as other pharmacokinetic characteristics). Individual enantiomer profiling revealed that the inhibitory potency primarily resided with the dextrorotatory eutomer (+)-22 (IC50 4.99 ± 0.18 nM). For the latter, a crystal structure of its complex with a C-terminal domain of sEH was obtained and resolved. These data fully validate (+)-22 as a new non-racemic advanced lead compound for further development as a potential therapeutic agent for use in such areas as cardiovascular disease, inflammation and pain.

AB - Spirocyclic 1-oxa-9-azaspiro[5.5]undecan-4-amine scaffold was explored as a basis for the design of potential inhibitors of soluble epoxide hydrolase (sEH). Synthesis and testing of the initial SAR-probing library followed by biochemical testing against sEH allowed nominating a racemic lead compound (±)-22. The latter showed remarkable (> 0.5 mM) solubility in aqueous phosphate buffer solution, unusually low (for sEH inhibitors) lipophilicity as confirmed by experimentally determined logD7.4 of 0.99, and an excellent oral bioavailability in mice (as well as other pharmacokinetic characteristics). Individual enantiomer profiling revealed that the inhibitory potency primarily resided with the dextrorotatory eutomer (+)-22 (IC50 4.99 ± 0.18 nM). For the latter, a crystal structure of its complex with a C-terminal domain of sEH was obtained and resolved. These data fully validate (+)-22 as a new non-racemic advanced lead compound for further development as a potential therapeutic agent for use in such areas as cardiovascular disease, inflammation and pain.

KW - 1-Oxa-9-azaspiro[5.5]undecan-4-amine

KW - Distomer

KW - Eutomer

KW - Low LogD

KW - Oral bioavailability

KW - Orthogonal periphery group variation

KW - Phosphate buffer solubility

KW - Prins reaction

KW - Protein-ligand crystal structure

KW - Spirocyclic

UR - http://www.scopus.com/inward/record.url?scp=85050458242&partnerID=8YFLogxK

U2 - 10.1016/j.bioorg.2018.07.014

DO - 10.1016/j.bioorg.2018.07.014

M3 - Article

AN - SCOPUS:85050458242

VL - 80

SP - 655

EP - 667

JO - Bioorganic Chemistry

JF - Bioorganic Chemistry

SN - 0045-2068

ER -

ID: 34633116