Delving into the Latest Updates on LY-3031207 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

LY 3031207, LY3031207

Target

PGES

Action

inhibitors

Mechanism

PGES inhibitors(Prostaglandin E synthase inhibitors)

Therapeutic Areas-

Active Indication-

Inactive Indication-

Originator Organization

Eli Lilly & Co.

Active Organization-

Inactive Organization

Eli Lilly & Co.

License Organization-

Drug Highest PhaseDiscontinuedPhase 1

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC16H19ClN4O2

InChIKeyMBAHGUNQNAJTLD-UHFFFAOYSA-N

CAS Registry1381846-21-4

The purposes of this study are to look at safety, how well the study drug is tolerated, how much of the study drug gets into the blood stream, and how long it takes the body to get rid of it when given to healthy Japanese and non-Japanese participants as multiple doses. In addition, effects of 28-day oral dosing of LY3031207 on the amount of a cholesterol-lowering drug (simvastatin) that gets into the blood stream and how long the body takes to get rid of it will be determined. The effects of LY3031207 after single and 28-day dosing on blood pressure will also be studied. Information about any side effects that may occur will be collected.

Start Date01 Jun 2012

Sponsor / Collaborator

Eli Lilly & Co.

NCT01449630

/ CompletedPhase 1

A Single-Dose, Dose-Escalation Study to Evaluate the Safety and Tolerability of LY3031207 in Healthy Subjects

This is a phase I study of LY3031207 in healthy subjects. The purposes of this study are to look at safety, how well the study drug is tolerated, and how much of the study drug gets into the blood stream and how long it takes the body to get rid of it when given to humans. Information about any side effects that may occur will also be collected. Subjects will participate in the study for approximately 3 months. This study is for research purposes only and is not intended to treat any medical condition.

Start Date24 Oct 2011

Sponsor / Collaborator

Eli Lilly & Co.

100 Clinical Results associated with LY-3031207

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100 Translational Medicine associated with LY-3031207

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100 Patents (Medical) associated with LY-3031207

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6

Literatures (Medical) associated with LY-3031207

01 Sep 2019·Bioorganic & medicinal chemistry lettersQ4 · MEDICINE

Discovery and optimization of pyridyl-cycloalkyl-carboxylic acids as inhibitors of microsomal prostaglandin E synthase-1 for the treatment of endometriosis

Q4 · MEDICINE

Article

Author: Coelho, Anne-Marie ; Nagel, Jens ; Ter Laak, Antonius ; Koppitz, Marcus ; Rotgeri, Andrea ; Peters, Michaele ; Bräuer, Nico ; Steinmeyer, Andreas ; Irlbacher, Horst ; Walter, Daryl ; Zollner, Thomas M

Here we report on novel and potent pyridyl-cycloalkyl-carboxylic acid inhibitors of microsomal prostaglandin E synthase-1 (PTGES). PTGES produces, as part of the prostaglandin pathway, prostaglandin E2 which is a well-known driver for pain and inflammation. This fact together with the observed upregulation of PTGES during inflammation suggests that blockade of the enzyme might provide a beneficial treatment option for inflammation related conditions such as endometriosis. Compound 5a, a close analogue of the screening hit, potently inhibited PTGES in vitro, displayed excellent PK properties in vitro and in vivo and demonstrated efficacy in a CFA-induced pain model in mice and in a rat dyspareunia endometriosis model and was therefore selected for further studies.

08 Mar 2018·Journal of medicinal chemistryQ1 · MEDICINE

Identification and Mitigation of Reactive Metabolites of 2-Aminoimidazole-Containing Microsomal Prostaglandin E Synthase-1 Inhibitors Terminated Due to Clinical Drug-Induced Liver Injury

Q1 · MEDICINE

Article

Author: Schiffler, Matthew A. ; Hughes, Norman E. ; Alberts, Jeffrey J. ; Norman, Bryan H. ; Fisher, Matthew J. ; Cassidy, Kenneth C. ; Abraham, Trent L. ; Czeskis, Boris A. ; Kuklish, Steven L. ; Luffer-Atlas, Debra

Two 2-aminoimidazole-based inhibitors, LY3031207 (1) and LY3023703 (2), of the microsomal prostaglandin E synthase-1 (mPGES-1) enzyme were found to cause drug-induced liver injury (DILI) in humans. We studied imidazole ring substitutions to successfully mitigate reactive metabolite (RM) formation. These studies support the conclusion that RM formation may play a role in the observations of DILI and the consideration of 2-aminoimidazoles as structure alerts, due to the high likelihood of bioactivation to generate RMs.

01 Jan 2018·British journal of clinical pharmacology

Dose‐dependent acute liver injury with hypersensitivity features in humans due to a novel microsomal prostaglandin E synthase 1 inhibitor

Article

Author: Regev, Arie ; Campanale, Kristina ; McNearney, Terry Ann ; Hall, D. Greg ; Landschulz, William ; Phipps, Krista ; Kam, Jeanelle ; Nakano, Masako ; Uetrecht, Jack ; Yang, Xiao Yan ; Smith, Claire ; Hu, Leijun ; Jin, Yan ; Henck, Judith

Aims:

LY3031207, a novel microsomal prostaglandin E synthase 1 inhibitor, was evaluated in a multiple ascending dose study after nonclinical toxicology studies and a single ascending dose study demonstrated an acceptable toxicity, safety and tolerability profile.

Methods:

Healthy subjects were randomized to receive LY3031207 (25, 75 and 275 mg), placebo or celecoxib (400 mg) once daily for 28 days. The safety, tolerability and pharmacokinetic and pharmacodynamic profiles of LY3031207 were evaluated.

Results:

The study was terminated when two subjects experienced drug‐induced liver injury (DILI) after they had received 225 mg LY3031207 for 19 days. Liver biopsy from these subjects revealed acute liver injury with eosinophilic infiltration. Four additional DILI cases were identified after LY3031207 dosing had been stopped. All six DILI cases shared unique presentations of hepatocellular injury with hypersensitivity features and demonstrated a steep dose‐dependent trend. Prompt discontinuation of the study drug and supportive medical care resulted in full recovery. Metabolites from metabolic activation of the imidazole ring were observed in plasma and urine samples from all subjects randomized to LY3031207 dosing.

Conclusions:

This study emphasized the importance of careful safety monitoring and serious adverse events management in phase I trials. Metabolic activation of the imidazole ring may be involved in the development of hepatotoxicity of LY3031207.

100 Deals associated with LY-3031207

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R&D Status

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT01449630 (CTgov)	Phase 1	-	29	Placebo	qbnsnogddt = hrmafnjmln iianodayew (qfjgmucfgu, wdoqrzfesk - ifvywwujri) View more	-	05 Jul 2019
NCT01632566 (CTgov)	Phase 1	-	39	LY3031207 (25 mg LY3031207)	bcvhxsgqrf = vgwzdtoehy mivphkfepv (ewawhlaais, uachwufnes - pdbvhndphr) View more	-	27 Jun 2019
NCT01632566 (CTgov)	Phase 1	-	39	Simvastatin+LY3031207 (75 mg LY3031207 and Simvastatin)	bcvhxsgqrf = crohszbtee mivphkfepv (ewawhlaais, zkxevxljhg - jvgielafsq) View more	-	27 Jun 2019