Dirlotapide

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Dirlotapide
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Executive Summary Information

Compound Dirlotapide (Slentrol)
Toxicities Steatosis
Mechanisms Dirlotapide is reversible Microsomal Triglyceride Transfer Protein (MTTP) inhibitor that blocks the assembly and release of lipoprotein particles from the liver into the blood.
Comments Dirlotapide was selected as a model compound to induce steatosis without accompanying chemical reactivity or promiscuous modulation of multiple proteins.
Feedback Contact Gold Compound Working Group (GCWG)
Dirlotapide
Dirlotapide.png


Identifiers
CAS 481658-94-0
ChemSpider 8093509
UNII 578H0RMP25
Pathway DBs
KEGG D03867
Assay DBs
PubChem CID 9917862
ChEMBL CHEMBL410414
Omics DBs
Properties
ToxCast Accepted no
ToxBank Accepted yes
Approved on 2012-05-01
Target MTTP inhibitor
Toxicities Steatosis


In Vivo Data ? Compound Assessment
Adverse Events ? Dirlotapide inhibits liver MTTP in humans and its utility is limited due to the elevation of transaminases at doses that are effective in blocking absorption of lipids in the intestine.

The most extensive adverse event studies are available for dogs. Elevations in hepatic transaminase activity were seen in dogs treated with more than 1.5 mg/kg dirlotapide daily in a 3 months study, but were not associated with clinical signs or microscopic evidence of hepatic degeneration or necrosis. Dirlotapide increases the risk of producing hepatic lipidosis during weight loss in obese cats.

In a 1 year study in dogs with lower doses from 0.1 to 0.2 mg/kg daily, a mild increase in mean ALT and AST activity was observed, which remained well within the published reference range for these analytes (ALT: 2 to 102 U/L, AST: 23 to 66 U/L). ALT activity tended to gradually increase as the dirlotapide dose increased during the first 6 months of weight loss and then decreased during the next 6 months despite continued dirlotapide treatment at the weight stabilization dosage. Gamma glutamyl transferase and total bilirubin were not changed.

References:

-Robinson R.P., et al., “Discovery of microsomal triglyceride transfer protein (MTTP) inhibitors with potential for decreased active metabolite load compared to dirlotapide”, Bioorganic & Medical Chemistry Letters, 21 (2011) 4150-4154
-Klonoff D.C., “Dirlotapide, a U.S. Food and Drug Administration-Approved First-in- Class Obesity Drug for Dogs—Will Humans Be Next?”, Journal of Diabetes Science and Technology, Volume 1, Issue 3, 314-316, May 2007
-J A Wren et al, “Dirlotapide: a review of its properties and role in the management of obesity in dogs”, J Vet Pharmacol Ther. 2007 Aug ;30 Suppl 1 :43-54
Toxicity Mechanisms ? Liver enzymes elevation is believed to be due to mechanism-related triglyceride (TG) accumulation and is associated with structurally diverse MTTP inhibitors, supporting an MTTP- based mechanism. For example, the MTTP inhibitor BMS 201038 caused elevation of hepatic fat in all subjects of the study after 4 weeks treatment.

References:

-Robinson R.P., Bioorganic & Medical Chemistry Letters, 21 (2011) 4150-4154
-Klonoff D.C., Journal of Diabetes Science and Technology, Volume 1, Issue 3, 314-316, May 2007
Therapeutic Target ? Dirlotapide was designed to be an MTTP inhibitor. The MTTP transporter is found in enterocytes, where it is responsible for uptake of chylomicrons in the intestines, and in the liver, where it secretes triglycerides to the blood. A gut-selective inhibitor is desirable for weight loss, whereas the net effect of inhibition of the liver transporter seems to be hepatotoxicity involving steatosis. Selectivity of dirlotapide for gut vs. liver is species-specific and related to the efficiency of absorption as well as binding to the transporter. The desired intestinal selectivity is observed in dogs but not in humans.

References:

PK-ADME ? Compound Assessment
PK parameters ? In vivo data is available for dog, rat, and monkey. In dog, systemic blood levels do not directly correlate with effectiveness since effectiveness is linked to drug concentrations in the gut. Dirlotapide is available systemically, but absorption is highly variable. Blood levels do correlate with the systemic toxicity observed for this drug.

The compound is very highly protein bound in plasma with free fraction = 0.0097%.

In beagle dogs dirlotapide exhibited low clearance, low first-pass metabolism, moderate volume of distribution, low-to-moderate oral bioavailability, a modest food effect, and variable accumulation. It is metabolized in the liver. Dirlotapide and its metabolites are secreted in the bile and may undergo enterohepatic circulation. The fecal and biliary routes are the predominant routes of elimination. Large interanimal variability in systemic exposure was noted for all routes and doses.

 0.3 mg/kg, i.v. 
     CLp = 7.8 mL/min/kg 
     Vd = 1.3 L/kg 
 0.3 mg/kg, po (uptake is saturable) 
     Cmax = 46 ng/mL 
     Bioavailability = 22-41% 
     tmax = 1.6 h 

The mean elimination half-life ranges between 5 and 18 hours and increases with dose and with repeated dosing. Human in vitro studies: Turnover in human microsomes with projected hepatic excretion (ER) 35%, hepatic CLh = 7.8 mL/min/kg

References:

-Jin Li et al, Bioorganic & Medical Chemistry Letters 17, (2007) 1996-1999
-Merritt DA et al, ” Absorption, distribution, metabolism, and excretion of dirlotapide in the dog”. J Vet Pharmacol Ther. 2007 Aug;30 Suppl 1:17-23.
-Jin Li et al, “In vitro and in vivo profile of 5-[(40-trifluoromethyl-biphenyl-2-carbonyl)- amino]-1H-indole-2-carboxylic acid benzylmethylcarbamoylamide (dirlotapide), a novel potent MTTP inhibitor for obesity”, Bioorganic & Medical Chemistry Letters 17, (2007) 1996-1999
-Merritt DA et al, ” Dirlotapide: a review of its properties and role in the management of obesity in dogs”, J Vet Pharmacol Ther. 2007 Aug;30 Suppl 1:24- 32.
-EMA EPAR Scientific Discussion
Therapeutic window ? Not relevant. The therapeutic window is determined by selectivity of dirlotapide for gut vs. liver, is species-specific, and is related to the efficiency of absorption as well as binding to the transporter. Described systemic toxicities are presumed to derive from on-target inhibition of liver MTTP.
Metabolically activated ? Metabolism of dirlotapide is generally considered to be inactivating.

After oral administration of 0.2mg/kg/d for 3 days the parent drug and two primary metabolites were observed in dogs' plasma (ca. 89% of total). After administration of 2.5mg/ kg once, more than 20 metabolites were observed in plasma. Cmax for 14C in radiolabel studies was 2- to 3-fold greater than parent dirlotapide. Dirlotapide is extensively metabolized by the liver. The major metabolic pathways are oxidative metabolism, N-dealkylation, and glucuronide and sulfate conjugation of metabolites.

References:

-Merritt DA et al, ” Dirlotapide: a review of its properties and role in the management of obesity in dogs”, J Vet Pharmacol Ther. 2007 Aug;30 Suppl 1:24-32.

In humans, dirlotapide gives rise to metabolites, specifically the products of mono and bis N- dealkylation at the terminal amide nitrogen. These accumulate and circulate at concentrations 2–7 fold higher than parent. These compounds also circulate as major metabolites in rats and dogs and retain activity against MTTP (unbound potencies ca. 30-fold less than parent). CYP3A is the predominant CYP mediated metabolic pathway based on inhibition of turnover in human liver microsomes using specific CYP inhibitors.

References:

-Robinson R.P., Bioorganic & Medical Chemistry Letters, 21 (2011) 4150-4154 Jin Li et al, Bioorganic & Medical Chemistry Letters 17, (2007) 1996-1999

Omics and IC50 Data ? Compound Assessment
Gene expression profiles known. ? Data not available
Proteomics profiles known. ? Data not available
Metabonomics profiles known. ? References:
-Sun, H. et al. Bioorg. Med. Chem. Lett. (2011), doi:10.1016/j.bmcl.2011.10.121
-Bessire AJ et al, Rapid Commun Mass Spectrom. 2010 Jul 30;24(14):2151-61.
Fluxomics profiles known. ? References:
-Sun, H. et al. Bioorg. Med. Chem. Lett. (2011), doi:10.1016/j.bmcl.2011.10.121
-Bessire AJ et al, Rapid Commun Mass Spectrom. 2010 Jul 30;24(14):2151-61.
Epigenomics profiles known. ? Data not available
Observed IC50 for in vitro cellular efficacy. ?
Observed IC50 for in vitro cellular toxicity studies. ?
  • IC50 = 1.5 nM for the inhibition of Apo B secretion from human HepG2 cells
  • IC50 = 4 nM for the inhibition of Apo B secretion in human HepG2 cells after 40 hrs by ELISA
  • IC50 = 2.9 nM for the inhibition of Apo B secretion in canine hepatocytes.
  • IC50 = 2 nM for inhibition of MTTP from dog liver microsomes by scintillation counting

References:

-Jin Li et al, Bioorganic & Medical Chemistry Letters 17, (2007) 1996-1999)
-PubChem
-Vu, C.B. et al, Bioorganic and Medicinal Chemistry Letters, Volume 19, Issue 5, 1 March 2009, Pages 1416-1420

Physical Properties ? Compound Assessment
Accepted and listed within the ToxCast/Tox21 program. ? No - Not included in ToxCast Phase I and II Chemicals List
Substance stability. ? Chemically and physically stable when stored below 30oC (commercial oral solution in oil)

References:

-EMA EPAR Scientific Discussion
Soluble in buffer solution at 30 times the in vitro IC50 for toxicity. ? Supplied clinically as solution in medium chain triglyceride oil. The solubility in water should be expected to be <100 uM. Dilute directly from DMSO solution whenever possible and avoid serial dilution from aqueous solutions. Recommend using at concentrations of 1 uM or less.
Solubility in DMSO 100 times buffer solubility. ? Data not available
Vessel binding properties. ? Highly probable
Vapor pressure. (Non-volatile) ? Non volatile


Authors of this ToxBank wiki page

David Bower
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