Identification of New Non-BBB Permeable Tryptophan Hydroxylase Inhibitors for Treating Obesity and Fatty Liver Disease

Suvarna H. Pagire; Haushabhau S. Pagire; Kun Young Park; Eun Jung Bae; Kwang Eun Kim; Minhee Kim; Jihyeon Yoon; Saravanan Parameswaran; Jun Ho Choi; Sungmi Park; Jae Han Jeon; Jin Sook Song; Myung Ae Bae; In Kyu Lee; Hail Kim; Jae Myoung Suh; Jin Hee Ahn

doi:10.3390/molecules27113417

Identification of New Non-BBB Permeable Tryptophan Hydroxylase Inhibitors for Treating Obesity and Fatty Liver Disease

Suvarna H. Pagire, Haushabhau S. Pagire, Kun Young Park, Eun Jung Bae, Kwang Eun Kim, Minhee Kim, Jihyeon Yoon, Saravanan Parameswaran, Jun Ho Choi, Sungmi Park, Jae Han Jeon, Jin Sook Song, Myung Ae Bae, In Kyu Lee, Hail Kim, Jae Myoung Suh, Jin Hee Ahn

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

5 Scopus citations

Abstract

Serotonin (5-hydroxytryptophan) is a hormone that regulates emotions in the central nervous system. However, serotonin in the peripheral system is associated with obesity and fatty liver disease. Because serotonin cannot cross the blood-brain barrier (BBB), we focused on identify-ing new tryptophan hydroxylase type I (TPH1) inhibitors that act only in peripheral tissues for treating obesity and fatty liver disease without affecting the central nervous system. Structural optimization inspired by para-chlorophenylalanine (pCPA) resulted in the identification of a series of oxyphenylalanine and heterocyclic phenylalanine derivatives as TPH1 inhibitors. Among these compounds, compound 18i with an IC50 value of 37 nM was the most active in vitro. Additionally, compound 18i showed good liver microsomal stability and did not significantly inhibit CYP and Herg. Furthermore, this TPH1 inhibitor was able to actively interact with the peripheral system without penetrating the BBB. Compound 18i and its prodrug reduced body weight gain in mam-mals and decreased in vivo fat accumulation.

Original language	English
Article number	3417
Journal	Molecules
Volume	27
Issue number	11
DOIs	https://doi.org/10.3390/molecules27113417
State	Published - 1 Jun 2022

Keywords

fatty liver
obesity
treatment
tryptophan hydroxylase inhibitor

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.3390/molecules27113417

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Pagire, S. H., Pagire, H. S., Park, K. Y., Bae, E. J., Kim, K. E., Kim, M., Yoon, J., Parameswaran, S., Choi, J. H., Park, S., Jeon, J. H., Song, J. S., Bae, M. A., Lee, I. K., Kim, H., Suh, J. M., & Ahn, J. H. (2022). Identification of New Non-BBB Permeable Tryptophan Hydroxylase Inhibitors for Treating Obesity and Fatty Liver Disease. Molecules, 27(11), Article 3417. https://doi.org/10.3390/molecules27113417

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title = "Identification of New Non-BBB Permeable Tryptophan Hydroxylase Inhibitors for Treating Obesity and Fatty Liver Disease",

abstract = "Serotonin (5-hydroxytryptophan) is a hormone that regulates emotions in the central nervous system. However, serotonin in the peripheral system is associated with obesity and fatty liver disease. Because serotonin cannot cross the blood-brain barrier (BBB), we focused on identify-ing new tryptophan hydroxylase type I (TPH1) inhibitors that act only in peripheral tissues for treating obesity and fatty liver disease without affecting the central nervous system. Structural optimization inspired by para-chlorophenylalanine (pCPA) resulted in the identification of a series of oxyphenylalanine and heterocyclic phenylalanine derivatives as TPH1 inhibitors. Among these compounds, compound 18i with an IC50 value of 37 nM was the most active in vitro. Additionally, compound 18i showed good liver microsomal stability and did not significantly inhibit CYP and Herg. Furthermore, this TPH1 inhibitor was able to actively interact with the peripheral system without penetrating the BBB. Compound 18i and its prodrug reduced body weight gain in mam-mals and decreased in vivo fat accumulation.",

keywords = "fatty liver, obesity, treatment, tryptophan hydroxylase inhibitor",

author = "Pagire, {Suvarna H.} and Pagire, {Haushabhau S.} and Park, {Kun Young} and Bae, {Eun Jung} and Kim, {Kwang Eun} and Minhee Kim and Jihyeon Yoon and Saravanan Parameswaran and Choi, {Jun Ho} and Sungmi Park and Jeon, {Jae Han} and Song, {Jin Sook} and Bae, {Myung Ae} and Lee, {In Kyu} and Hail Kim and Suh, {Jae Myoung} and Ahn, {Jin Hee}",

note = "Publisher Copyright: {\textcopyright} 2022 by the authors. Licensee MDPI, Basel, Switzerland.",

year = "2022",

month = jun,

day = "1",

doi = "10.3390/molecules27113417",

language = "English",

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Pagire, SH, Pagire, HS, Park, KY, Bae, EJ, Kim, KE, Kim, M, Yoon, J, Parameswaran, S, Choi, JH, Park, S, Jeon, JH, Song, JS, Bae, MA, Lee, IK, Kim, H, Suh, JM & Ahn, JH 2022, 'Identification of New Non-BBB Permeable Tryptophan Hydroxylase Inhibitors for Treating Obesity and Fatty Liver Disease', Molecules, vol. 27, no. 11, 3417. https://doi.org/10.3390/molecules27113417

TY - JOUR

T1 - Identification of New Non-BBB Permeable Tryptophan Hydroxylase Inhibitors for Treating Obesity and Fatty Liver Disease

AU - Pagire, Suvarna H.

AU - Pagire, Haushabhau S.

AU - Park, Kun Young

AU - Bae, Eun Jung

AU - Kim, Kwang Eun

AU - Kim, Minhee

AU - Yoon, Jihyeon

AU - Parameswaran, Saravanan

AU - Choi, Jun Ho

AU - Park, Sungmi

AU - Jeon, Jae Han

AU - Song, Jin Sook

AU - Bae, Myung Ae

AU - Lee, In Kyu

AU - Kim, Hail

AU - Suh, Jae Myoung

AU - Ahn, Jin Hee

PY - 2022/6/1

Y1 - 2022/6/1

N2 - Serotonin (5-hydroxytryptophan) is a hormone that regulates emotions in the central nervous system. However, serotonin in the peripheral system is associated with obesity and fatty liver disease. Because serotonin cannot cross the blood-brain barrier (BBB), we focused on identify-ing new tryptophan hydroxylase type I (TPH1) inhibitors that act only in peripheral tissues for treating obesity and fatty liver disease without affecting the central nervous system. Structural optimization inspired by para-chlorophenylalanine (pCPA) resulted in the identification of a series of oxyphenylalanine and heterocyclic phenylalanine derivatives as TPH1 inhibitors. Among these compounds, compound 18i with an IC50 value of 37 nM was the most active in vitro. Additionally, compound 18i showed good liver microsomal stability and did not significantly inhibit CYP and Herg. Furthermore, this TPH1 inhibitor was able to actively interact with the peripheral system without penetrating the BBB. Compound 18i and its prodrug reduced body weight gain in mam-mals and decreased in vivo fat accumulation.

AB - Serotonin (5-hydroxytryptophan) is a hormone that regulates emotions in the central nervous system. However, serotonin in the peripheral system is associated with obesity and fatty liver disease. Because serotonin cannot cross the blood-brain barrier (BBB), we focused on identify-ing new tryptophan hydroxylase type I (TPH1) inhibitors that act only in peripheral tissues for treating obesity and fatty liver disease without affecting the central nervous system. Structural optimization inspired by para-chlorophenylalanine (pCPA) resulted in the identification of a series of oxyphenylalanine and heterocyclic phenylalanine derivatives as TPH1 inhibitors. Among these compounds, compound 18i with an IC50 value of 37 nM was the most active in vitro. Additionally, compound 18i showed good liver microsomal stability and did not significantly inhibit CYP and Herg. Furthermore, this TPH1 inhibitor was able to actively interact with the peripheral system without penetrating the BBB. Compound 18i and its prodrug reduced body weight gain in mam-mals and decreased in vivo fat accumulation.

KW - fatty liver

KW - obesity

KW - treatment

KW - tryptophan hydroxylase inhibitor

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U2 - 10.3390/molecules27113417

DO - 10.3390/molecules27113417

M3 - Article

C2 - 35684355

AN - SCOPUS:85131181024

SN - 1420-3049

VL - 27

JO - Molecules

JF - Molecules

IS - 11

M1 - 3417

ER -

Identification of New Non-BBB Permeable Tryptophan Hydroxylase Inhibitors for Treating Obesity and Fatty Liver Disease

Abstract

Keywords

UN SDGs

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