Details of the Drug-Related molecule(s) Interaction Atlas

General Information of Drug (ID: DM8IL1U)

• Drug Name: Gavestinel Drug Info
• Synonyms: UNII-318X4QY113; 153436-22-7; GV 150526X; GV-150526X; 318X4QY113; 1H-Indole-2-carboxylic acid, 4,6-dichloro-3-(3-oxo-3-(phenylamino)-1-propenyl)-, (E)-; 4,6-Dichloro-3-((E)-2-(phenylcarbamoyl)vinyl)indole-2-carboxylic acid; 1H-Indole-2-carboxylic acid, 4,6-dichloro-3-((1E)-3-oxo-3-(phenylamino)-1-propenyl)-; (E)-4,6-Dichloro-3-(3-oxo-3-(phenylamino)-1-propenyl)-1H-indole-2-carboxylic acid; GV 150526; Gavestinel (USAN/INN); AC1O51WR; Gavestinel [USAN:INN:BAN]; CHEMBL44793; SCHEMBL678632; SCHEMBL1721070

Indication

Disease Entry	ICD 11	Status	REF
Nerve injury	ND56.4	Discontinued in Phase 2	[1]

• Cross-matching ID:
  PubChem CID: 6450546
  ChEBI ID: CHEBI:92867
  CAS Number: CAS 153436-22-7
  TTD Drug ID: DM8IL1U
  INTEDE Drug ID: DR0763

Molecule-Related Drug Atlas

Drug(s) Targeting Glycine receptor (GlyR)

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
THIOCOLCHICOSIDE	DMEPWYA	Muscle spasm	MB47.3	Approved	[4]
ZD-9379	DM3KYO4	Cerebrovascular ischaemia	8B1Z	Phase 1	[5]
UK-240455	DMSCXB7	Nerve injury	ND56.4	Phase 1	[6]
MDL-27531	DMC60S8	Epilepsy	8A60-8A68	Phase 1	[7]
GV-196771	DMFN21T	Migraine	8A80	Discontinued in Phase 2	[8]
GW 468816	DMQ92WF	Tobacco dependence	6C4A.2	Discontinued in Phase 2	[9]
M-241247	DMIY51U	Cerebrovascular ischaemia	8B1Z	Terminated	[10]
GINKOLIDE B	DMLIM7B	Sepsis	1G40-1G41	Terminated	[11]
3-demethoxy-3-D-lyxopyranosylaminothiocolchicine	DME8VPC	Discovery agent	N.A.	Investigative	[4]
3-demethoxy-3-D-xylopyranosylaminothiocolchicine	DMXFVD1	Discovery agent	N.A.	Investigative	[4]

Drug(s) Metabolized By UDP-glucuronosyltransferase 1A1 (UGT1A1)

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Tamoxifen	DMLB0EZ	Breast cancer	2C60-2C65	Approved	[12]
Estradiol	DMUNTE3	Acne vulgaris	ED80	Approved	[13]
Acetaminophen	DMUIE76	Allergic rhinitis	CA08.0	Approved	[14]
Etoposide	DMNH3PG	Acute myelogenous leukaemia	2A41	Approved	[15]
Zidovudine	DM4KI7O	Human immunodeficiency virus infection	1C62	Approved	[16]
Valproate	DMCFE9I	Epilepsy	8A60-8A68	Approved	[17]
Mycophenolate mofetil	DMPQAGE	Hepatosplenic T-cell lymphoma		Approved	[18]
Metronidazole	DMTIVEN	Abscess		Approved	[19]
Propofol	DMB4OLE	Anaesthesia	9A78.6	Approved	[20]
Ethanol	DMDRQZU	Chronic pain	MG30	Approved	[21]

Drug(s) Metabolized By UDP-glucuronosyltransferase 1A3 (UGT1A3)

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Diclofenac	DMPIHLS	Chronic renal failure	GB61.Z	Approved	[22]
Valproate	DMCFE9I	Epilepsy	8A60-8A68	Approved	[17]
Ibuprofen	DM8VCBE	Dysmenorrhea	GA34.3	Approved	[3]
Atorvastatin	DMF28YC	Acute coronary syndrome	BA41	Approved	[23]
Cerivastatin	DMXCM7H	Hyperlipidaemia	5C80	Approved	[24]
PITAVASTATIN CALCIUM	DM1UJO0	Dyslipidemia	5C80-5C81	Approved	[25]
Troglitazone	DM3VFPD	Diabetic complication	5A2Y	Approved	[26]
Ezetimibe	DM7A8TW	Atherosclerosis	BD40	Approved	[27]
Simvastatin	DM30SGU	Arteriosclerosis	BD40	Approved	[28]
Losartan	DM72JXH	Diabetic kidney disease	GB61.Z	Approved	[3]

Drug(s) Metabolized By UDP-glucuronosyltransferase 1A9 (UGT1A9)

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Acetaminophen	DMUIE76	Allergic rhinitis	CA08.0	Approved	[29]
Diclofenac	DMPIHLS	Chronic renal failure	GB61.Z	Approved	[22]
Sorafenib	DMS8IFC	Adenocarcinoma	2D40	Approved	[30]
Valproate	DMCFE9I	Epilepsy	8A60-8A68	Approved	[3]
Mycophenolate mofetil	DMPQAGE	Hepatosplenic T-cell lymphoma		Approved	[31]
Propofol	DMB4OLE	Anaesthesia	9A78.6	Approved	[3]
Ibuprofen	DM8VCBE	Dysmenorrhea	GA34.3	Approved	[3]
Troglitazone	DM3VFPD	Diabetic complication	5A2Y	Approved	[32]
Nateglinide	DMLK2QH	Diabetic complication	5A2Y	Approved	[3]
Haloperidol	DM96SE0	Delirium		Approved	[3]

Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
Glycine receptor (GlyR)	TTZ8EM9	GLRA1_HUMAN; GLRA2_HUMAN; GLRA3_HUMAN; GLRA4_HUMAN; GLRB_HUMAN	Modulator	[2]

Drug-Metabolizing Enzyme (DME)

DME Name	DME ID	UniProt ID	MOA	REF
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Substrate	[3]
UDP-glucuronosyltransferase 1A9 (UGT1A9)	DE85D2P	UD19_HUMAN	Substrate	[3]
UDP-glucuronosyltransferase 1A3 (UGT1A3)	DEF2WXN	UD13_HUMAN	Substrate	[3]

References

• [1] Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800007924)
• [2] Glycine antagonist (gavestinel) in neuroprotection (GAIN International) in patients with acute stroke: a randomised controlled trial.GAIN International Investigators.Lancet.2000 Jun 3;355(9219):1949-54.
• [3] Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675.
• [4] 3-demethoxy-3-glycosylaminothiocolchicines: Synthesis of a new class of putative muscle relaxant compounds. J Med Chem. 2006 Sep 7;49(18):5571-7.
• [5] Neuroprotective potential of ionotropic glutamate receptor antagonists. Neurotox Res. 2002 Mar;4(2):119-26.
• [6] UK-315716/UK-240455. Pfizer. Curr Opin Investig Drugs. 2001 Dec;2(12):1737-9.
• [7] MDL 27,531 reduces spontaneous hindlimb contractions in rats with chronic transections of the spinal cord. Neurosci Lett. 1992 Nov 23;147(1):101-5.
• [8] First time in human for GV196771: interspecies scaling applied on dose selection. J Clin Pharmacol. 1999 Jun;39(6):560-6.
• [9] A double-blind, placebo-controlled trial of the NMDA glycine site antagonist, GW468816, for prevention of relapse to smoking in females.J Clin Psychopharmacol.2011 Oct;31(5):597-602.
• [10] Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800003415)
• [11] Probing the pharmacophore of ginkgolides as glycine receptor antagonists. J Med Chem. 2007 Apr 5;50(7):1610-7.
• [12] Functional significance of UDP-glucuronosyltransferase variants in the metabolism of active tamoxifen metabolites. Cancer Res. 2009 Mar 1;69(5):1892-900.
• [13] Functional characterization of human and cynomolgus monkey UDP-glucuronosyltransferase 1A1 enzymes. Life Sci. 2010 Aug 14;87(7-8):261-8.
• [14] Effect of UDP-glucuronosyltransferase (UGT) 1A polymorphism (rs8330 and rs10929303) on glucuronidation status of acetaminophen. Dose Response. 2017 Sep 11;15(3):1559325817723731.
• [15] UDP-glucuronosyltransferase 1A1 is the principal enzyme responsible for etoposide glucuronidation in human liver and intestinal microsomes: structural characterization of phenolic and alcoholic glucuronides of etoposide and estimation of enzyme kinetics. Drug Metab Dispos. 2007 Mar;35(3):371-80.
• [16] Interindividual variability in pharmacokinetics of generic nucleoside reverse transcriptase inhibitors in TB/HIV-coinfected Ghanaian patients: UGT2B7*1c is associated with faster zidovudine clearance and glucuronidation. J Clin Pharmacol. 2009 Sep;49(9):1079-90.
• [17] Effect of aging on glucuronidation of valproic acid in human liver microsomes and the role of UDP-glucuronosyltransferase UGT1A4, UGT1A8, and UGT1A10. Drug Metab Dispos. 2009 Jan;37(1):229-36.
• [18] Characterization of rat intestinal microsomal UDP-glucuronosyltransferase activity toward mycophenolic acid. Drug Metab Dispos. 2006 Sep;34(9):1632-9.
• [19] Drug-drug interactions for UDP-glucuronosyltransferase substrates: a pharmacokinetic explanation for typically observed low exposure (AUCi/AUC) ratios. Drug Metab Dispos. 2004 Nov;32(11):1201-8.
• [20] Substrate-dependent modulation of UDP-glucuronosyltransferase 1A1 (UGT1A1) by propofol in recombinant human UGT1A1 and human liver microsomes. Basic Clin Pharmacol Toxicol. 2007 Sep;101(3):211-4.
• [21] Identification and preliminary characterization of UDP-glucuronosyltransferases catalyzing formation of ethyl glucuronide. Anal Bioanal Chem. 2014 Apr;406(9-10):2325-32.
• [22] Glucuronidation of nonsteroidal anti-inflammatory drugs: identifying the enzymes responsible in human liver microsomes. Drug Metab Dispos. 2005 Jul;33(7):1027-35.
• [23] UGT1A1*28 is associated with decreased systemic exposure of atorvastatin lactone. Mol Diagn Ther. 2013 Aug;17(4):233-7.
• [24] Cerivastatin, genetic variants, and the risk of rhabdomyolysis. Pharmacogenet Genomics. 2011 May;21(5):280-8.
• [25] Pitavastatin: a review in hypercholesterolemia. Am J Cardiovasc Drugs. 2017 Apr;17(2):157-168.
• [26] Troglitazone glucuronidation in human liver and intestine microsomes: high catalytic activity of UGT1A8 and UGT1A10. Drug Metab Dispos. 2002 Dec;30(12):1462-9.
• [27] Drug interactions between the immunosuppressant tacrolimus and the cholesterol absorption inhibitor ezetimibe in healthy volunteers. Clin Pharmacol Ther. 2011 Apr;89(4):524-8.
• [28] Pharmacogenomics of statins: understanding susceptibility to adverse effects. Pharmgenomics Pers Med. 2016 Oct 3;9:97-106.
• [29] Polymorphic expression of UGT1A9 is associated with variable acetaminophen glucuronidation in neonates: a population pharmacokinetic and pharmacogenetic study. Clin Pharmacokinet. 2018 Oct;57(10):1325-1336.
• [30] Pharmacokinetic interaction involving sorafenib and the calcium-channel blocker felodipine in a patient with hepatocellular carcinoma. Invest New Drugs. 2011 Dec;29(6):1511-4.
• [31] The evolution of population pharmacokinetic models to describe the enterohepatic recycling of mycophenolic acid in solid organ transplantation and autoimmune disease. Clin Pharmacokinet. 2011 Jan;50(1):1-24.
• [32] The UDP-glucuronosyltransferase 1A9 enzyme is a peroxisome proliferator-activated receptor alpha and gamma target gene. J Biol Chem. 2003 Apr 18;278(16):13975-83.