title: Tryptophan hydroxylase 1 Inhibition Impacts Pulmonary Vascular Remodeling in Two Rat Models of Pulmonary Hypertension.
abstract: Pulmonary arterial hypertension (PAH) is a progressive disease defined by a chronic elevation in pulmonary arterial pressure with extensive pulmonary vascular remodeling and perivascular inflammation characterized by an accumulation of macrophages, lymphocytes, dendritic cells, and mast cells. Although the exact etiology of the disease is unknown, clinical as well as preclinical data strongly implicate a role for serotonin (5-HT) in the process. Here, we investigated the chronic effects of pharmacological inhibition of tryptophan hydroxylase 1 (TPH1), the rate-limiting enzyme in peripheral 5-HT biosynthesis, in two preclinical models of pulmonary hypertension (PH), the monocrotaline (MCT) rat and the semaxanib (SUGEN, Medinoah, Suzhou, China)-hypoxia rat. In both PH models, ethyl (S)-8-(2-amino-6-((R)-1-(5-chloro-[1,1'-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate and ethyl (S)-8-(2-amino-6-((R)-1-(3',4'-dimethyl-3-(3-methyl-1 H-pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate, novel orally active TPH1 inhibitors with nanomolar in vitro potency, decreased serum, gut, and lung 5-HT levels in a dose-dependent manner and significantly reduced pulmonary arterial pressure, and pulmonary vessel wall thickness and occlusion in male rats. In the MCT rat model, decreases in lung 5-HT significantly correlated with reductions in histamine levels and mast cell number (P < 0.001, r2= 0.88). In contrast, neither ambrisentan nor tadalafil, which are vasodilators approved for the treatment of PAH, reduced mast cell number or 5-HT levels, nor were they as effective in treating the vascular remodeling as were the TPH1 inhibitors. When administered in combination with ambrisentan, the TPH1 inhibitors showed an additive effect on pulmonary vascular remodeling and pressures. These data demonstrate that in addition to reducing vascular remodeling, TPH1 inhibition has the added benefit of reducing the perivascular mast cell accumulation associated with PH.
authors.affiliation: Karos Pharmaceuticals, New Haven, Connecticut (R.J.A, P.-A.B, Q.Z, J.D., D.R.G., S.D.L., V.P.); INSERM UMR_S 999, Le Plessis-Robinson, France (M.H., C.G.), Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France (M.H., C.G.); Service de Pneumologie, Hôpital Bicêtre, Assistance Publique Hôpitaux de Paris, Le Kremlin-Bicêtre, France (M.H.); Division of Cardiology and Consortium for Fibrosis Research and Translation, Department of Medicine, University of Colorado Denver, Aurora, Colorado (M.A.C., T.A.M.) raiello@karospharma.com.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Aiello
authors.affiliation: Karos Pharmaceuticals, New Haven, Connecticut (R.J.A, P.-A.B, Q.Z, J.D., D.R.G., S.D.L., V.P.); INSERM UMR_S 999, Le Plessis-Robinson, France (M.H., C.G.), Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France (M.H., C.G.); Service de Pneumologie, Hôpital Bicêtre, Assistance Publique Hôpitaux de Paris, Le Kremlin-Bicêtre, France (M.H.); Division of Cardiology and Consortium for Fibrosis Research and Translation, Department of Medicine, University of Colorado Denver, Aurora, Colorado (M.A.C., T.A.M.).
authors.forename: Patricia-Ann
authors.initials: PA
authors.lastname: Bourassa
authors.affiliation: Karos Pharmaceuticals, New Haven, Connecticut (R.J.A, P.-A.B, Q.Z, J.D., D.R.G., S.D.L., V.P.); INSERM UMR_S 999, Le Plessis-Robinson, France (M.H., C.G.), Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France (M.H., C.G.); Service de Pneumologie, Hôpital Bicêtre, Assistance Publique Hôpitaux de Paris, Le Kremlin-Bicêtre, France (M.H.); Division of Cardiology and Consortium for Fibrosis Research and Translation, Department of Medicine, University of Colorado Denver, Aurora, Colorado (M.A.C., T.A.M.).
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Karos Pharmaceuticals, New Haven, Connecticut (R.J.A, P.-A.B, Q.Z, J.D., D.R.G., S.D.L., V.P.); INSERM UMR_S 999, Le Plessis-Robinson, France (M.H., C.G.), Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France (M.H., C.G.); Service de Pneumologie, Hôpital Bicêtre, Assistance Publique Hôpitaux de Paris, Le Kremlin-Bicêtre, France (M.H.); Division of Cardiology and Consortium for Fibrosis Research and Translation, Department of Medicine, University of Colorado Denver, Aurora, Colorado (M.A.C., T.A.M.).
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Dubins
authors.affiliation: Karos Pharmaceuticals, New Haven, Connecticut (R.J.A, P.-A.B, Q.Z, J.D., D.R.G., S.D.L., V.P.); INSERM UMR_S 999, Le Plessis-Robinson, France (M.H., C.G.), Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France (M.H., C.G.); Service de Pneumologie, Hôpital Bicêtre, Assistance Publique Hôpitaux de Paris, Le Kremlin-Bicêtre, France (M.H.); Division of Cardiology and Consortium for Fibrosis Research and Translation, Department of Medicine, University of Colorado Denver, Aurora, Colorado (M.A.C., T.A.M.).
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Goldberg
authors.affiliation: Karos Pharmaceuticals, New Haven, Connecticut (R.J.A, P.-A.B, Q.Z, J.D., D.R.G., S.D.L., V.P.); INSERM UMR_S 999, Le Plessis-Robinson, France (M.H., C.G.), Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France (M.H., C.G.); Service de Pneumologie, Hôpital Bicêtre, Assistance Publique Hôpitaux de Paris, Le Kremlin-Bicêtre, France (M.H.); Division of Cardiology and Consortium for Fibrosis Research and Translation, Department of Medicine, University of Colorado Denver, Aurora, Colorado (M.A.C., T.A.M.).
authors.forename: Stéphane
authors.initials: S
authors.lastname: De Lombaert
authors.affiliation: Karos Pharmaceuticals, New Haven, Connecticut (R.J.A, P.-A.B, Q.Z, J.D., D.R.G., S.D.L., V.P.); INSERM UMR_S 999, Le Plessis-Robinson, France (M.H., C.G.), Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France (M.H., C.G.); Service de Pneumologie, Hôpital Bicêtre, Assistance Publique Hôpitaux de Paris, Le Kremlin-Bicêtre, France (M.H.); Division of Cardiology and Consortium for Fibrosis Research and Translation, Department of Medicine, University of Colorado Denver, Aurora, Colorado (M.A.C., T.A.M.).
authors.forename: Marc
authors.initials: M
authors.lastname: Humbert
authors.affiliation: Karos Pharmaceuticals, New Haven, Connecticut (R.J.A, P.-A.B, Q.Z, J.D., D.R.G., S.D.L., V.P.); INSERM UMR_S 999, Le Plessis-Robinson, France (M.H., C.G.), Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France (M.H., C.G.); Service de Pneumologie, Hôpital Bicêtre, Assistance Publique Hôpitaux de Paris, Le Kremlin-Bicêtre, France (M.H.); Division of Cardiology and Consortium for Fibrosis Research and Translation, Department of Medicine, University of Colorado Denver, Aurora, Colorado (M.A.C., T.A.M.).
authors.forename: Christophe
authors.initials: C
authors.lastname: Guignabert
authors.affiliation: Karos Pharmaceuticals, New Haven, Connecticut (R.J.A, P.-A.B, Q.Z, J.D., D.R.G., S.D.L., V.P.); INSERM UMR_S 999, Le Plessis-Robinson, France (M.H., C.G.), Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France (M.H., C.G.); Service de Pneumologie, Hôpital Bicêtre, Assistance Publique Hôpitaux de Paris, Le Kremlin-Bicêtre, France (M.H.); Division of Cardiology and Consortium for Fibrosis Research and Translation, Department of Medicine, University of Colorado Denver, Aurora, Colorado (M.A.C., T.A.M.).
authors.forename: Maria A
authors.initials: MA
authors.lastname: Cavasin
authors.affiliation: Karos Pharmaceuticals, New Haven, Connecticut (R.J.A, P.-A.B, Q.Z, J.D., D.R.G., S.D.L., V.P.); INSERM UMR_S 999, Le Plessis-Robinson, France (M.H., C.G.), Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France (M.H., C.G.); Service de Pneumologie, Hôpital Bicêtre, Assistance Publique Hôpitaux de Paris, Le Kremlin-Bicêtre, France (M.H.); Division of Cardiology and Consortium for Fibrosis Research and Translation, Department of Medicine, University of Colorado Denver, Aurora, Colorado (M.A.C., T.A.M.).
authors.forename: Timothy A
authors.initials: TA
authors.lastname: McKinsey
authors.affiliation: Karos Pharmaceuticals, New Haven, Connecticut (R.J.A, P.-A.B, Q.Z, J.D., D.R.G., S.D.L., V.P.); INSERM UMR_S 999, Le Plessis-Robinson, France (M.H., C.G.), Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France (M.H., C.G.); Service de Pneumologie, Hôpital Bicêtre, Assistance Publique Hôpitaux de Paris, Le Kremlin-Bicêtre, France (M.H.); Division of Cardiology and Consortium for Fibrosis Research and Translation, Department of Medicine, University of Colorado Denver, Aurora, Colorado (M.A.C., T.A.M.).
authors.forename: Vishwas
authors.initials: V
authors.lastname: Paralkar
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D006976:Hypertension, Pulmonary / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D011651:Pulmonary Artery / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000097:blood / Q000378:metabolism; D014365:Tryptophan Hydroxylase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D066253:Vascular Remodeling / Q000187:drug effects*
chemical_list: D004791:Enzyme Inhibitors; D012701:Serotonin; D014365:Tryptophan Hydroxylase