General
Preferred name
GLIMEPIRIDE
Synonyms
GLIMEPIRIDEn/a ()
Glimperide ()
HOE-490 ()
HOE 490 ()
Amaryl ()
Niddaryl ()
NSC-759809 ()
P&D ID
PD000671
CAS
93479-97-1
Tags
natural product
drug
available
Approved by
FDA
First approval
1995
Drug Status
approved
Max Phase
Phase 4
Drug indication
Hypoglycemic
Structure
Probe scores
P&D probe-likeness score
[[ v.score ]]%
Structure formats
[[ format ]]
[[ compound[format === 'MOL' ? 'molblock' : format.toLowerCase()] ]]
Description
(extracted from source data)
PHARMACODYNAMICS Glimepiride stimulates the secretion of insulin granules from the pancreatic beta cells and improves the sensitivity of peripheral tissues to insulin to increase peripheral glucose uptake, thus reducing plasma blood glucose levels and glycated hemoglobin (HbA1C) levels. A multicenter, randomized, placebo-controlled clinical trial evaluated the efficacy of glimepiride (1–8 mg) as monotherapy titrated over 10 weeks compared with placebo in T2DM subjects who were not controlled by diet alone [A177703]. In this study, there was a reduction in fasting plasma glucose (FPG) by 46 mg/dL, post-prandial glucose (PPG) by 72 mg/dL, and HbA1c by 1.4% more than the placebo [A177703]. In another randomized study comprising of patients with T2DM receiving either placebo or one of the three doses (1, 4, or 8 mg) of glimepiride during a 14-week study period, all glimepiride regimens significantly reduced FPG, PPG, and HbA1c values (P < 0.001) compared to placebo by the end of the study period [A177703]. The 4- and 8-mg doses of glimepiride were more effective than the 1-mg dose; however, the 4-mg dose provided a nearly maximal antihyperglycemic effect [A177703].
INDICATION Glimepiride is indicated for the management of type 2 diabetes in adults as an adjunct to diet and exercise to improve glycemic control as monotherapy. It may also be indicated for use in combination with metformin or insulin to lower blood glucose in patients with type 2 diabetes whose high blood sugar levels cannot be controlled by diet and exercise in conjunction with an oral hypoglycemic (a drug used to lower blood sugar levels) agent alone [F4540].
ROE Following oral administration of glimepiride in healthy male subjects, approximately 60% of the total radioactivity was recovered in the urine in 7 days, with M1 and M2 accounting for 80-90% of the total radioactivity recovered in the urine. The ratio of M1 to M2 was approximately 3:2 in two subjects and 4:1 in one subject [FDA Label]. Approximately 40% of the total radioactivity was recovered in feces where M1 and M2 accounted for about 70% of the radioactivity and a ratio of M1 to M2 being 1:3. No parent drug was recovered from urine or feces [FDA Label].
TOXICITY The oral LD50 value in rats is > 10000 mg/kg [MSDS]. The intraperitoneal LD50 value in rats is reported to be 3950 mg/kg [MSDS].; Although glimepiride is reported to have fewer risks of hypoglycemia compared to other sulfonylureas such as glyburide, overdosage of glimepiride may result in severe hypoglycemia with coma, seizure, or other neurological impairment may occur. This can be treated with glucagon or intravenous glucose. Continued observation and additional carbohydrate intake may be necessary since hypoglycemia may recur after apparent clinical recovery [FDA Label]. ; ; In a study of rats given doses of up to 5000 parts per million (ppm) in complete feed for 30 months, there were no signs of carcinogenesis. Meanwhile, the administration of glimepiride at a dose much higher than the maximum human recommended dose for 24 months in mice resulted in an increase in benign pancreatic adenoma formation in a dose-related manner, which was thought to be the result of chronic pancreatic stimulation [FDA Label]. Glimepiride was non-mutagenic in a battery of in vitro and in vivo mutagenicity studies. In male and female rat studies, glimepiride was shown to have no effects on fertility [FDA Label].
METABOLISM Glimepiride is reported to undergo hepatic metabolism. Following either an intravenous or oral dose, glimepiride undergoes oxidative biotransformation mediated by CYP2C9 enzyme to form a major metabolite, cyclohexyl hydroxymethyl derivative (M1), that is pharmacologically active. M1 can be further metabolized to the inactive metabolite carboxyl derivative (M2) by one or several cytosolic enzymes. M1 retained approximately one third of the pharmacologic activity of its parent in an animal model, with a half-life of 3-6 hours [A177715]. However, whether the glucose-lowering effect of M1 is clinically significant is not clear.
HALF-LIFE The elimination half-life of glimepiride is approximately 5 to 8 hours [A177715], which can increase up to 9 hours following multiple doses [A177709].
MOA ATP-sensitive potassium channels on pancreatic beta cells that are gated by intracellular ATP and ADP. The hetero-octomeric complex of the channel is composed of four pore-forming Kir6.2 subunits and four regulatory sulfonylurea receptor (SUR) subunits. Alternative splicing allows the formation of channels composed of varying subunit isoforms expressed at different concentrations in different tissues [A177730]. In pancreatic beta cells, ATP-sensitive potassium channels play a role as essential metabolic sensors and regulators that couple membrane excitability with glucose-stimulated insulin secretion (GSIS) [A177727]. When there is a decrease in the ATP:ADP ratio, the channels are activated and open, leading to K+ efflux from the cell, membrane hyperpolarization, and suppression of insulin secretion [A177727]. In contrast, increased uptake of glucose into the cell leads to elevated intracellular ATP:ADP ratio, leading to the closure of channels and membrane depolarization. Depolarization leads to activation and opening of the voltage-dependent Ca2+ channels and consequently an influx of calcium ions into the cell [A177727]. Elevated intracellular calcium levels causes the contraction of the filaments of actomyosin responsible for the exocytosis of insulin granules stored in vesicles [A177715]. Glimepiride blocks the ATP-sensitive potassium channel by binding non-specifically to the B sites of both sulfonylurea receptor-1 (SUR1) and sulfonylurea receptor-2A (SUR2A) subunits as well as the A site of SUR1 subunit of the channel [A177715] to promote insulin secretion from the beta cell.
ABSORPTION Glimepiride is completely absorbed after oral administration within 1 hour of administration with a linear pharmacokinetics profile [A177703]. Following administration of a single oral dose of glimepiride in healthy subjects and with multiple oral doses with type 2 diabetes, the peak plasma concentrations (Cmax) were reached after 2 to 3 hours post-dose [FDA Label]. Accumulation does not occur after multiple doses [A177703]. When glimepiride was given with meals, the time to reach Cmax was increased by 12% while the mean and AUC (area under the curve) were decreased by 8 to 9%, respectively [F4540]. In a pharmacokinetic study of Japanese patients with T2DM, Cmax value in once-daily dose was higher than those in twice-daily doses [A177724]. The absolute bioavailability of glimepiride is reported to be complete following oral administration [A177721].
DESCRIPTION Only approved by the EMA (2007) to be used in combination with pioglitazone (Tandemact®). Note that the PubChem CID listed above refers to the non-isomeric molecule. We show the isomeric form which corresponds to the structure held with the INN record for this compound. (GtoPdb)
DESCRIPTION KATP channel blocker (Tocriscreen Total)
Compound Sets
21
Cayman Chemical Bioactives
12090
ChEMBL Approved Drugs
CHEMBL1481
ChEMBL Drugs
CHEMBL1481
Drug Repurposing Hub
DrugBank
DB00222
DrugBank Approved Drugs
DB00222
DrugCentral
1300
DrugCentral Approved Drugs
1300
Enamine BioReference Compounds
Guide to Pharmacology
6820
Mcule NIBR MoA Box Subset
MCULE-3589962187
MedChem Express Bioactive Compound Library
HY-B0104
NCATS Inxight Approved Drugs
6KY687524K
NIH Clinical Collections (NCC)
Novartis Chemogenetic Library (NIBR MoA Box)
NPC Screening Collection
Prestwick Chemical Library
ReFrame library
Selleckchem Bioactive Compound Library
Glimepiride
The Spectrum Collection
Tocriscreen Total
External IDs
33
Properties
(calculated by RDKit )
Molecular Weight
490.22
Hydrogen Bond Acceptors
5
Hydrogen Bond Donors
3
Rotatable Bonds
7
Ring Count
3
Aromatic Ring Count
1
cLogP
3.07
TPSA
124.68
Fraction CSP3
0.54
Chiral centers
0.0
Largest ring
6.0
QED
0.54
Structural alerts
0
No structural alerts detected
Related compounds
Custom attributes
(extracted from source data)
Member status
member
MOA
K(ATP) Channel Blockers
insulin secretagogue
Indication
diabetes mellitus
Target
ABCC8, KCNJ1, KCNJ11
Amyloid-β
Potassium Channel
Pathway
Neuronal Signaling
Source data