Discovery of a potent, dual serotonin and norepinephrine reuptake inhibitor.
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SUBMITTER: Dreyfus N
PROVIDER: S-EPMC4027471 | biostudies-literature | 2013 Jun
REPOSITORIES: biostudies-literature
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Discovery of a potent, dual serotonin and norepinephrine reuptake inhibitor.
Dreyfus Nicolas N Myers Jason K JK Badescu Valentina O VO de Frutos Oscar O de la Puente Maria Luz ML Ding Chunjin C Filla Sandra A SA Fynboe Karsten K Gernert Douglas L DL Heinz Beverly A BA Hemrick-Luecke Susan K SK Johnson Kirk W KW Johnson Michael P MP López Pilar P Love Patrick L PL Martin Laura J LJ Masquelin Thierry T McCoy Michael J MJ Mendiola Javier J Morrow Denise D Muhlhauser Mark M Pascual Gustavo G Perun Thomas J TJ Pfeifer Lance A LA Phebus Lee A LA Richards Simon J SJ Rincón Juan Antonio JA Seest Eric P EP Shah Jikesh J Shaojuan Jia J Simmons Rosa Maria A RM Stephenson Gregory A GA Tromiczak Eric G EG Thompson Linda K LK Walter Magnus W MW Weber Wayne W WW Zarrinmayeh Hamideh H Thomas Craig E CE Joshi Elizabeth E Iyengar Smriti S Johansson Anette M AM
ACS medicinal chemistry letters 20130507 6
The objective of the described research effort was to identify a novel serotonin and norepinephrine reuptake inhibitor (SNRI) with improved norepinephrine transporter activity and acceptable metabolic stability and exhibiting minimal drug-drug interaction. We describe herein the discovery of a series of 3-substituted pyrrolidines, exemplified by compound 1. Compound 1 is a selective SNRI in vitro and in vivo, has favorable ADME properties, and retains inhibitory activity in the formalin model of ...[more]
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Project description:Importance:In 2006, the US Food and Drug Administration (FDA) issued an advisory warning on the risk of serotonin syndrome with concomitant use of triptans and selective serotonin reuptake inhibitor (SSRI) or selective norepinephrine reuptake inhibitor (SNRI) antidepressants, but the true risk of serotonin syndrome in these patients remains unknown. Objective:To assess the risk of serotonin syndrome with concomitant use of triptans and SSRI or SNRI antidepressants. Design, Setting, and Participants:This study used electronic health record data from the Partners Research Data Registry (RPDR) to identify patients who had received an International Classification of Diseases, Ninth Revision diagnosis compatible with serotonin syndrome who had been coprescribed triptans and SSRI or SNRI antidepressants in the Greater Boston, Massachusetts, area from January 1, 2001, through December 31, 2014 (14 years). Clinical information was extracted to determine whether the case met formal diagnostic criteria and had coprescription within a calendar year. Both conservative and broad case definitions were used to better characterize the spectrum of risk. Data analysis was performed from November 23, 2016, to July 15, 2017. Main Outcomes and Measures:Incidence of serotonin syndrome. Results:The RPDR search revealed 47?968 (±3) unique patients who were prescribed triptans during the 14-year period of the study. A total of 19?017 (±3) patients were coprescribed triptans and antidepressants during the study, with a total of 30?928 person-years of exposure. Serotonin syndrome was suspected in 17 patients. Only 2 patients were classified as having definite serotonin syndrome (incidence rate, 0.6 cases per 10?000 person-years of exposure; 95% CI, 0.0-1.5). Five patients were classified as having possible serotonin syndrome (incidence rate with these 5 cases added to the 2 definite cases, 2.3 cases per 10?000 person-years of exposure; 95% CI, 0.6-3.9). The proportion of patients with triptan prescriptions who were coprescribed an SSRI or SNRI antidepressant was relatively stable during the study, ranging from 21% to 29%. Conclusions and Relevance:The risk of serotonin syndrome associated with concomitant use of triptans and SSRIs or SNRIs was low. Coprescription of these drugs is common and did not decrease after the 2006 FDA advisory. Our results cast doubt on the validity of the FDA advisory and suggest that it should be reconsidered.
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Project description:LY2878735 is a novel dual serotonin (5-hydroxytryptamine (5-HT)) and norepinephrine (NE) reuptake inhibitor (SNRI) in development for chronic pain indications. In vitro profile suggests a more balanced profile as compared with other SNRI's, which is expected to confer superior clinical efficacy. LY2878735 is metabolized partly by the genetically polymorphic cytochrome P450 (CYP) 2D6 pathway, raising pharmacokinetic (PK) variability concerns. Phase 1 PK and biomarker data were analyzed by pharmacometric methods to characterize the balance between dual-target engagement and adverse effects on heart rate (HR) and blood pressure (BP). A narrow range of plasma LY2878735 levels was associated with an acceptable balance. As compared with poor metabolizers (PM), CYP2D6 extensive metabolizers (EM) have 21- and threefold higher clearance and distribution volume, respectively. Even with a CYP2D6-based dosing paradigm, a superior therapeutic index comparable to duloxetine, a widely used SNRI, was not achievable and LY2878735 development was thus terminated. Model-based approach effectively synthesizes PK-pharmacodynamic (PD) relationships, enabling efficient early development decisions.CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e66; doi:10.1038/psp.2013.43; published online 21 August 2013.
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Project description:8kand a serotonin/norepinephrine reuptake inhibitor.7jshowed that the regions spanning transmembrane domain (TM)1, TM3, and TM6 form the ligand binding pocket. The compound.8kbound tightly to the binding pocket of all three monoamine reuptake transporters; however.7jshowed poor docking with DAT. Co-expression of DAT with the dopamine D2 receptor (D2R) significantly inhibited DA-induced endocytosis of D2R probably by reuptaking DA into the cells. Pretreatment of the cells with.8f, which is one of the compounds with good inhibitory activity on DAT, blocked DAT-induced inhibition of D2R endocytosis. In summary, this study identified critical structural features contributing to the selectivity of a molecule for each of the monoamine transporters, critical residues on the compounds that bound to the transporters, and the functional role of a DA reuptake inhibitor in regulating D2R function.
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