Optimization of spirocyclic proline tryptophan hydroxylase-1 inhibitors.

Authors :: Goldberg DR
De Lombaert S
Aiello R
Bourassa P
Barucci N
Zhang Q
Paralkar V
Stein AJ
Holt M
Valentine J
Zavadoski W
Source :: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2017 Feb 01; Vol. 27 (3), pp. 413-419. Date of Electronic Publication: 2016 Dec 23.
Publication Year :: 2017
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.<br /> (Copyright © 2016 Elsevier Ltd. All rights reserved.)