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
Affiliations
Suvarna H. Pagire
Department of Chemistry, Gwangju Institute of Science and Technology, Gwangju 61005, Korea
Haushabhau S. Pagire
Department of Chemistry, Gwangju Institute of Science and Technology, Gwangju 61005, Korea
Kun-Young Park
Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Korea
Eun Jung Bae
Department of Chemistry, Gwangju Institute of Science and Technology, Gwangju 61005, Korea
Kwang-eun Kim
Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Korea
Minhee Kim
Department of Chemistry, Gwangju Institute of Science and Technology, Gwangju 61005, Korea
Jihyeon Yoon
Department of Chemistry, Gwangju Institute of Science and Technology, Gwangju 61005, Korea
Saravanan Parameswaran
Department of Chemistry, Gwangju Institute of Science and Technology, Gwangju 61005, Korea
Jun-Ho Choi
Department of Chemistry, Gwangju Institute of Science and Technology, Gwangju 61005, Korea
Sungmi Park
Leading-Edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Hospital, Daegu 41404, Korea
Jae-Han Jeon
Leading-Edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Hospital, Daegu 41404, Korea
Jin Sook Song
Bio and Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34141, Korea
Myung Ae Bae
Bio and Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34141, Korea
In-Kyu Lee
Leading-Edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Hospital, Daegu 41404, Korea
Hail Kim
Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Korea
Jae Myoung Suh
Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Korea
Jin Hee Ahn
Department of Chemistry, Gwangju Institute of Science and Technology, Gwangju 61005, Korea
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 identifying 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 mammals and decreased in vivo fat accumulation.
