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.
Subject(s)
Prodrugs/chemistry , Proline/analogs & derivatives , Pyrimidines/chemistry , Spiro Compounds/chemistry , Tryptophan Hydroxylase/antagonists & inhibitors , Tryptophan Hydroxylase/metabolism , Animals , Binding Sites , Dogs , Half-Life , Humans , Inhibitory Concentration 50 , Intestinal Mucosa/metabolism , Intestines/drug effects , Mice , Molecular Docking Simulation , Prodrugs/metabolism , Prodrugs/pharmacology , Proline/metabolism , Proline/pharmacology , Protein Structure, Tertiary , Pyrimidines/metabolism , Pyrimidines/pharmacology , Rats , Serotonin/metabolism , Spiro Compounds/metabolism , Spiro Compounds/pharmacology , Structure-Activity RelationshipABSTRACT
An increasing number of diseases have been linked to a dysfunctional peripheral serotonin system. Given that tryptophan hydroxylase 1 (TPH1) is the rate limiting enzyme in the biosynthesis off serotonin, it represents an attractive target to regulate peripheral serotonin. Following up to our first disclosure, we report a new chemotype of TPH1 inhibitors where-by the more common central planar heterocycle has been replaced with an open-chain, acyl guanidine surrogate. Through our work, we found that compounds of this nature provide highly potent TPH1 inhibitors with favorable physicochemical properties that were effective in reducing murine intestinal 5-HT in vivo. Furthermore, we obtained a high resolution (1.90Å) X-ray structure crystal structure of one of these inhibitors (compound 51) that elucidated the active conformation along with revealing a dimeric form of TPH1 for the first time.
Subject(s)
Drug Discovery , Enzyme Inhibitors/pharmacology , Guanidine/pharmacology , Tryptophan Hydroxylase/antagonists & inhibitors , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Guanidine/chemical synthesis , Guanidine/chemistry , Humans , Models, Molecular , Molecular Structure , Structure-Activity Relationship , Tryptophan Hydroxylase/metabolismABSTRACT
In the changing climate of the NHS support workers such as health care assistants (HCAs) are becoming more prevalent in departments, wards and clinics throughout the National Health Service (NHS) including critical care and high dependency units (CCUs/HDUs) [Hind M, Jackson D, Andrewes C, Fulbrook P, Galvin K, Frost S. Health care support workers in the critical care setting. Nurs Crit Care 2000;5(1):31-9; Hogan J, Playle J. The utilization of the health care assistant role in intensive care. Br J Nurs 2000;9(12):794-801; Wainwright TA. The perceived function of health care assistants in intensive care: nurses views'. Intens Crit Care Nurs 2002;18:171-80]. The CCU within an acute hospital Trust in the South East of England, which employs HCAs undertook an audit to assess staff views on extending the role of the HCAs and ascertain the perceived implications of extending their role within the unit. A re-audit was undertaken after the implementation of changes recommended from the initial survey to review the impact on the CCU staff. A semi-structured questionnaire was designed based on the findings of previous studies and the recommendations identified through the evidence-based literature review. A response rate of 64% was achieved for the initial audit. A second questionnaire was designed after the implementation of initiatives proposed in the initial audit and a 58% response rate was achieved. The results from the first audit indicated support for the extended role of HCAs, staff perception of the current HCA role and identified key tasks staff felt were appropriate for HCAs to undertake as part of an extended role. However, opinions regarding the types of skills the HCAs should acquire in an extended role, the method and content of training and the perceived benefits and limitations of extending the HCAs role within the unit varied. The results of the second questionnaire indicated the majority of staff were aware of the changes implemented, approved of the changes and were positive about the impact on the unit but, required more detailed information about, and involvement in, the continued implementation of the changes.
