5TPG

Optimization of spirocyclic proline tryptophanhydroxylase-1 inhibitors

Summary for 5TPG

• Entry DOI: 10.2210/pdb5tpg/pdb
• Related: 5L01
• Descriptor: Tryptophan 5-hydroxylase 1, FE (III) ION, 2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL, ... (6 entities in total)
• Functional Keywords: tph1, iron, acyl, quanidine, oxidoreductase-inhibitor complex, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 36371.50

Authors

Stein, A.J.,Goldberg, D.R.,De Lombaert, S.,Holt, M.C. (deposition date: 2016-10-20, release date: 2017-01-25, Last modification date: 2024-03-06)

Primary citation

Goldberg, D.R.,De Lombaert, S.,Aiello, R.,Bourassa, P.,Barucci, N.,Zhang, Q.,Paralkar, V.,Stein, A.J.,Holt, M.,Valentine, J.,Zavadoski, W.
Optimization of spirocyclic proline tryptophan hydroxylase-1 inhibitors.
Bioorg. Med. Chem. Lett., 27:413-419, 2017

PubMed Abstract: As a follow-up to the discovery of our spirocyclic proline-based TPH1 inhibitor lead, we describe the optimization of this scaffold. Through a combination of X-ray co-crystal structure guided design and an in vivo screen, new substitutions in the lipophilic region of the inhibitors were identified. This effort led to new TPH1 inhibitors with in vivo efficacy when dosed as their corresponding ethyl ester prodrugs. In particular, 15b (KAR5585), the prodrug of the potent TPH1 inhibitor 15a (KAR5417), showed robust reduction of intestinal serotonin (5-HT) levels in mice. Furthermore, oral administration of 15b generated high and sustained systemic exposure of the active parent 15a in rats and dogs. KAR5585 was selected for further pharmacological evaluation in disease models associated with a dysfunctional peripheral 5-HT system.

PubMed: 28041831
DOI: 10.1016/j.bmcl.2016.12.053

Experimental method

X-RAY DIFFRACTION (1.5 Å)