ID: ALA1472

Max Phase: Approved

First Approval: 1976

Molecular Formula: C16H22N6O4

Molecular Weight: 362.39

Molecule Type: Protein

Representations

Synonyms (16): 5-oxo-pro-his-pro-nh2 | ABBOTT-38579 | Lopremone | Protirelin | Protirelin, synthetic | Relefact trh | Synthetic TRH | Thyroid releasing hormone | Thyroliberin | Thyrotropin releasing hormone | Thyrotropin-releasing factor | Thyrotropin-releasing hormone | A-38579 | ABBOTT-38579 | NSC-760113 | SYNTHETIC TRH
Synonyms from Alternative Forms(16):

Trade Names(3): Thypinone | Thyrel trh | Trh-cambridge

Canonical SMILES:  NC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H]1CCC(=O)N1

Standard InChI:  InChI=1S/C16H22N6O4/c17-14(24)12-2-1-5-22(12)16(26)11(6-9-7-18-8-19-9)21-15(25)10-3-4-13(23)20-10/h7-8,10-12H,1-6H2,(H2,17,24)(H,18,19)(H,20,23)(H,21,25)/t10-,11-,12-/m0/s1

Standard InChI Key:  XNSAINXGIQZQOO-SRVKXCTJSA-N

Molecule Features

Natural Product: Yes

Oral: No

Chemical Probe: No

Parenteral: Yes

Molecule Type: Protein

Topical: No

First In Class: No

Black Box: No

Chirality: Yes

Availability: No

Prodrug: No

Properties

Molecular Weight: 362.39

Molecular Weight (Monoisotopic): 362.1703

AlogP: -1.81

#Rotatable Bonds: 6

Polar Surface Area: 150.28

Molecular Species: NEUTRAL

HBA: 5

HBD: 4

#RO5 Violations: 0

HBA (Lipinski): 10

HBD (Lipinski): 5

#RO5 Violations (Lipinski): 0

CX Acidic pKa: 11.15

CX Basic pKa: 6.53

CX LogP: -2.93

CX LogD: -2.98

Aromatic Rings: 1

Heavy Atoms: 26

QED Weighted: 0.47

Np Likeness Score: -0.41

References

1. Rutledge LD, Perlman JH, Gershengorn MC, Marshall GR, Moeller KD..  (1996)  Conformationally restricted TRH analogs: a probe for the pyroglutamate region.,  39  (8): [PMID:8648595] [10.1021/jm960053k]

2. Szirtes T, Kisfaludy L, Pálosi E, Szporny L..  (1986)  Synthesis of thyrotropin-releasing hormone analogues. 2. Tripeptides structurally greatly differing from TRH with high central nervous system activity.,  29  (9): [PMID:3091831] [10.1021/jm00159a015]

3. Oshiro Y, Sakurai Y, Sato S, Kurahashi N, Tanaka T, Kikuchi T, Tottori K, Uwahodo Y, Miwa T, Nishi T..  (2000)  3,4-dihydro-2(1H)-quinolinone as a novel antidepressant drug: synthesis and pharmacology of 1-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-3,4- dihydro-5-methoxy-2(1H)-quinolinone and its derivatives.,  43  (2): [PMID:10649973] [10.1021/jm980333v]

4. Oshiro Y, Sakurai Y, Tanaka T, Ueda H, Kikuchi T, Tottori K..  (1991)  Novel cerebroprotective agents with central nervous system stimulating activity. 1. Synthesis and pharmacology of 1-amino-7-hydroxyindan derivatives.,  34  (7): [PMID:1676756] [10.1021/jm00111a013]

5. Oshiro Y, Sakurai Y, Tanaka T, Kikuchi T, Hirose T, Tottori K..  (1991)  Novel cerebroprotective agents with central nervous system stimulating activity. 2. Synthesis and pharmacology of the 1-(acylamino)-7-hydroxyindan derivatives.,  34  (7): [PMID:1676757] [10.1021/jm00111a014]

6. Suzuki M, Sugano H, Matsumoto K, Yamamura M, Ishida R..  (1990)  Synthesis and central nervous system actions of thyrotropin-releasing hormone analogues containing a dihydroorotic acid moiety.,  33  (8): [PMID:2115588] [10.1021/jm00170a014]

7. Mazurov AA, Andronati SA, Korotenko TI, Sokolenko NI, Dyadenko AI, Shapiro YE, Gorbatyuk VY, Voronina TA.  (1996)  Design of a novel cognitive enhancer (8S, 10aS)-8-carbamoyl-1,2,3,6,7,8,9,10a-octahydro-5H,10H-pyrrolo[1,2-a][1,4]diazocin-5,10-dione,  6  (21): [10.1016/0960-894X(96)00478-7]

8. Olson GL, Cheung HC, Chiang E, Madison VS, Sepinwall J, Vincent GP, Winokur A, Gary KA..  (1995)  Peptide mimetics of thyrotropin-releasing hormone based on a cyclohexane framework: design, synthesis, and cognition-enhancing properties.,  38  (15): [PMID:7636847] [10.1021/jm00015a009]

9. Chu W, Perlman JH, Gershengorn MC, Moeller KD..  (1998)  Thyrotropin releasing hormone analogs: a building block approach to the construction of tetracyclic peptidomimetics.,  8  (21): [PMID:9873682] [10.1016/s0960-894x(98)00567-8]

10. Goebel RJ, Currie BL, Bowers CY..  (1981)  Potential thyroliberin affinity labels. 1. Chloroacetyl-substituted phenylalanylpyrrolidines.,  24  (4): [PMID:6267279] [10.1021/jm00136a003]

11. Szirtes T, Kisfaludy L, Pálosi E, Szporny L..  (1984)  Synthesis of thyrotropin-releasing hormone analogues. 1. Complete dissociation of central nervous system effects from thyrotropin-releasing activity.,  27  (6): [PMID:6429332] [10.1021/jm00372a006]

12. Prokai L, Prokai-Tatrai K, Zharikova AD, Nguyen V, Perjesi P, Stevens SM..  (2004)  Centrally acting and metabolically stable thyrotropin-releasing hormone analogues by replacement of histidine with substituted pyridinium.,  47  (24): [PMID:15537357] [10.1021/jm020531t]

13. Kaur N, Lu X, Gershengorn MC, Jain R..  (2005)  Thyrotropin-releasing hormone (TRH) analogues that exhibit selectivity to TRH receptor subtype 2.,  48  (19): [PMID:16162016] [10.1021/jm0505462]

14. Kaur N, Monga V, Lu X, Gershengorn MC, Jain R..  (2007)  Modifications of the pyroglutamic acid and histidine residues in thyrotropin-releasing hormone (TRH) yield analogs with selectivity for TRH receptor type 2 over type 1.,  15  (1): [PMID:17035026] [10.1016/j.bmc.2006.09.045]

15. Wessling ST, Ross BP, Koda Y, Blanchfield JT, Toth I..  (2007)  Caco-2 cell permeability and stability of two d-glucopyranuronamide conjugates of thyrotropin-releasing hormone.,  15  (14): [PMID:17498958] [10.1016/j.bmc.2007.04.042]

16. Carroll AR, Lamb J, Moni R, Hooper JN, Quinn RJ..  (2008)  Spongian diterpenes with thyrotropin releasing hormone receptor 2 binding affinity from Spongia sp.,  71  (5): [PMID:18407692] [10.1021/np070658r]

17. Carroll AR, Urban S, Lamb J, Moni R, Guymer GP, Forster PI, Quinn RJ..  (2008)  Corymbones A and B, phloroglucinols with thyrotropin releasing hormone receptor 2 binding affinity from the flowers of Corymbia peltata.,  71  (5): [PMID:18412395] [10.1021/np0706567]

18. Unpublished dataset, 

19. PubChem BioAssay data set, 

20. USP Dictionary of USAN and International Names (2010 edition) and USAN registrations 2007-date, 

21. PubChem BioAssay data set, 

22. Meena CL, Thakur A, Nandekar PP, Sangamwar AT, Sharma SS, Jain R..  (2015)  Synthesis of CNS active thyrotropin-releasing hormone (TRH)-like peptides: Biological evaluation and effect on cognitive impairment induced by cerebral ischemia in mice.,  23  (17): [PMID:26216015] [10.1016/j.bmc.2015.07.022]

23. Meena CL, Thakur A, Nandekar PP, Sharma SS, Sangamwar AT, Jain R..  (2016)  Synthesis and biology of ring-modified l-Histidine containing thyrotropin-releasing hormone (TRH) analogues.,  111  [PMID:26854379] [10.1016/j.ejmech.2016.01.038]

24. WHO Anatomical Therapeutic Chemical Classification, 

25. British National Formulary (72nd edition), 

26.  (2010)  TRH-like peptide derivatives as inhibitors of the TRH-degrading ectoenzyme, 

27. Chen M, Suzuki A, Thakkar S, Yu K, Hu C, Tong W..  (2016)  DILIrank: the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans.,  21  (4): [PMID:26948801] [10.1016/j.drudis.2016.02.015]

28. Unpublished dataset, 

29. Franck Touret, Magali Gilles, Karine Barral, Antoine Nougairède, Etienne Decroly, Xavier de Lamballerie, Bruno Coutard.  (2020)  In vitro screening of a FDA approved chemical library reveals potential inhibitors of SARS-CoV-2 replication,  [10.1101/2020.04.03.023846]

30. Katie Heiser, Peter F. McLean, Chadwick T. Davis, Ben Fogelson, Hannah B. Gordon, Pamela Jacobson, Brett Hurst, Ben Miller, Ronald W. Alfa, Berton A. Earnshaw, Mason L. Victors, Yolanda T. Chong, Imran S. Haque, Adeline S. Low, Christopher C. Gibson.  (2020)  Identification of potential treatments for COVID-19 through artificial intelligence-enabled phenomic analysis of human cells infected with SARS-CoV-2,  [10.1101/2020.04.21.054387]

31.  (2021)  EUbOPEN Chemogenomics Library wave 1,  [10.6019/CHEMBL4689842]

32. EUbOPEN.  (2022)  EUbOPEN Chemogenomics Library wave 2 - DSF,  [10.6019/CHEMBL5060014]

33. EUbOPEN.  (2023)  GPCR results for EUbOPEN Chemogenomics Library 3,  [10.6019/CHEMBL5209801]

Source

Source(10):

• Scientific Literature
• PubChem BioAssays
• Clinical Candidates
• FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book)
• USP Dictionary of USAN and International Drug Names
• Patent Bioactivity Data
• WHO Anatomical Therapeutic Chemical Classification
• British National Formulary
• SARS-CoV-2 Screening Data 2020-21
• EUbOPEN Chemogenomic Library