1. International Nonproprietary Names (INN)
Tanta university
Faculty of pharmacy
Dept. of Pharm. Chem.
Pharmacy Seniors
2019/2020
Drug Design Tutorial # 5
International Nonproprietary Names (INN)

2. International Nonproprietary Names (INN)
As unique names, INN have to be distinctive in sound and spelling, and should not be liable to confusion with other names in common use. To make INN universally available they are formally placed by WHO in the public domain, hence their designation as "nonproprietary". They can be used without any restriction whatsoever to identify pharmaceutical substances.
Another important feature of the INN system is that the names of pharmacologically-related substances demonstrate their relationship by using a common "stem". By the use of common stems the medical practitioner, the pharmacist, or anyone dealing with pharmaceutical products can recognize that the substance belongs to a group of substances having similar pharmacological activity.

3. Selection of INN
The names which are given the status of an INN are selected by the World Health Organization on the advice of experts from the WHO Expert Advisory Panel on the International Pharmacopoeia and Pharmaceutical Preparations. The process of INN selection follows three main steps:
a request/application is made by the manufacturer or inventor; - after a review of the request a proposed INN is selected and published for comments; - after a time-period for objections has lapsed, the name will obtain the status of a recommended INN and will be published as such if no objection has been raised.
INN are selected in principle only for single, well-defined substances that can be unequivocally characterized by a chemical name (or formula).
An INN is usually designated for the active part of the molecule only

4. INN Lists

5. Guidance on the Use of International Nonproprietary Names (INNs) for Pharmaceutical Substances

6. Use of stems
Usually, an INN consists of a random, fantasy prefix and a common stem; substances belonging to a
group of pharmacologically related substances show their relationship by the use of a common stem.
Sometimes sub-stems are established to differentiate between different related groups of substances,
e.g.
-olol for β-adrenoreceptor antagonists and antihypertensive,
-teplase for tissue-type-plasminogen activators and
-uplase for urokinase-type-plasminogen activators.
-zomib………..for proteasome inhibitors (e.g. bortizomib)…………. Don’t confuse with (-mab)

7. Examples are: -anib ………for angiogenesis inhibitors (e.g. pazopanib)
-anserin …..for serotonin receptor antagonists, especially 5-HT2 antagonists (e.g. ritanserin and mianserin)
-arit ……….for antiarthritic agents (e.g. lobenzarit)
-ase ………for enzymes (e.g. alteplase)
-azepam …for benzodiazepines (e.g. diazepam and oxazepam)
-caine ……for local anaesthetics (e.g. procaine or cocaine)
-cain- …….for class I antiarrhythmics (e.g. procainamide)
-coxib ……for COX-2 inhibitors, a type of anti-inflammatory drugs (e.g. celecoxib)
-navir …….for antiretroviral protease inhibitors (e.g. darunavir)
-olol ………for beta blockers (e.g. atenolol)
-pril ……….for ACE inhibitors (e.g. captopril)
-sartan …...for angiotensin II receptor antagonists (e.g. losartan)
-tinib ……..for tyrosine kinase inhibitors (e.g. imatinib)
-vastatin …for HMG-CoA reductase inhibitors, a group of cholesterol lowering agents (e.g. simvastatin)
-vir ……….for antivirals (e.g. aciclovir or ritonavir)
arte- ……..for artemisinin antimalarials (e.g. artemether)
cef- ………for cefalosporins (e.g. cefalexin)
io- ………..for iodine-containing radiopharmaceuticals (e.g. iobenguane)

8. -tinib ……..for tyrosine kinase inhibitors (e.g. fedratinib)
-parib………for poly-ADP-ribose polymerase inhibitors (e.g. talazoparib)
-fenib …….for a protein kinase inhibitor, including VEGFR, PDGFR and RAF kinases (e.g. encorafenib)
-ciclib………for cyclin dependant kinase inhibitors (e.g. ribociclib)
-olone……for (see pred) steroids other than prednisolone derivatives (e.g. brexanolone)
-lisib ………for phosphatidylinositol 3-kinase inhibitors, antineoplastics (e.g. alpelisib)
-rsen………for antisense oligonucleotides (e.g. golodirsen)
-siran………for small interfering RNA (e.g. givosiran)
-pitant…….for (see -tant) neurokinin NK1 (substance P) receptor antagonist (e.g. fosnetupitant)
-virine……...for (see vir) non-nucleoside reverse transcriptase inhibitors (NNRTI) (e.g. doravirine)
-oxacin…….for antibacterials, nalidixic acid derivatives (e.g. delafloxacin)
-xaban…….for blood coagulation factor XA inhibitors, antithrombotics (e.g. betrixaban)
-anib……….for angiogenesis inhibitors
-bactam…..for β-lactamase inhibitors (e.g. vaborbactam)
-penem……for analogues of penicillanic acid antibiotics modified in the five-membered ring
(e.g. meropenem)
-tide………..for peptides and glycopeptides (for special groups of peptides see -actide, -pressin, -relin)
(e.g. bremelanotide)
-acetam….for (see -racetam) amide type nootrope agents, piracetam derivatives (e.g. brivaracetam)
-anserine….for serotonin receptor antagonists (mostly 5-HT2) (e.g. pimavanserin)
-azol >>>> antifungal
-bendazole…... anthelminthics, tiabendazole derivatives

9. Stereoisomers
An INN for a new chemical entity does not routinely specify the stereoisomeric state of the molecule in the nonproprietary name. If the stereochemistry has been determined, then this information is presented in the chemical name(s) to identify the substance.
An INN can, therefore, identify the racemic mixture (e.g. ibuprofen, tetramisole), the levo- isomer (e.g. amifostine, lofentanil, prenalterol, remoxipride, quadazocine), or the dextro form (e.g. butopamine). Subsequently if an INN is needed for a different enantiomer or for the racemic form, the following prefixes should be added to the existing INN:
a) For the levo form, the lev-/levo- prefix is used, ………e.g. levocarnitine, levamisole.
b) For the dextro form, the dex- prefix is used, ………….e.g. dexamisole, dexibuprofen.
c) For the racemic form, the rac-/race- prefix is used, …...e.g. racepinefrine.

10. Radioactive compounds
A name for a drug substance containing a radioactive atom should list, in the following order:
1) the name of the substance containing the radioactive atom,
2) the isotope number,
3) the element symbol, and
4) the name of the carrier agent, if any,
e.g.
Gallium dotatoc Ga-68
Fluorodopa F-18
Lutetium Lu 177 dotatate
fluciclovine F-18
Iobenguane I 131
cyanocobalamin (60 Co)
technetium (99m Tc) bicisate

11. Gallium dotatoc Ga-68
Edotreotide gallium Ga-68 is an 8 amino acid peptide bound to the chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA).8 Edotreotide gallium Ga-68 is indicated for localizing somatostatin receptor positive neuroendocrine tumors by positron emission tomography.
Gallium-68 (Ga 68) decays with a half-life of 68 minutes to stable Zn 68:
89% through positron emission with a mean energy of 836 keV

12. Fluorodopa F-18 decays by positron emission to Oxygen O 18 (stable)
has a physical half-life of minutes. The principal photons useful for imaging are the dual 511 keV gamma photons

13. fluciclovine F-18

14. Lutetium Lu 177 dotatate
Lutetium (Lu 177) decays to stable hafnium (Hf 177) with a half-life of days, by emitting beta radiation

15. iobenguane
I 131 decays with beta and gamma emissions with a physical half-life of days.
Iodine 123 decays to Te 123 (tellurium) by electron capture and has a physical half-life of 13.2 hours.

16. Guidance on the Use of International Nonproprietary Names (INNs) for biological and biotechnological substances

17. GENERAL POLICIES FOR BIOLOGICAL AND BIOTECHNOLOGICAL SUBSTANCES
General policy for non-glycosylated substances
General policy for glycosylated substances
General policy for pegylated substances
General policy for substances for gene therapy
General policy for substances for cell therapy
General policy for substances for cell-based gene therapy
General policy for substances for virus-based therapy
General policy for monoclonal antibodies
General policy for blood products
General policy for immunoglobulins fractionated from plasma
General policy for vaccines

18. General policy for non-glycosylated substances
For groups identified with a stem (e.g. -irudin for hirudin analogues) differences in the amino acid sequence are indicated by using a random prefix e.g. bivalirudin.
For groups identified with a word (e.g. insulin) differences in the amino acid sequence are indicated by using a second element (e.g. insulin argine.

19. Bivalirudin
Bivalirudin (Angiomax or Angiox, manufactured by The Medicines Company) is a direct thrombin inhibitor (DTI).
Chemically, it is a synthetic congener of the naturally occurring drug hirudin (found in the saliva of the medicinal leech Hirudo medicinalis).

20. Insulins
Up to now, insulin derivatives have been named using a two-word approach. The substances named represent a structure with an additional amino acid, such as insulin argine (58), or represent modifications of the amino acid sequence, i.e. insulin aspart.
Argine:…………. B30-yl-L-arginyl-L-arginine
aspart:…………. [B28-L-aspartic acid]
degludec:……... N6.B29-[N-(15-carboxypentadecanoyl)-L-γ-glutamyl]-des-30B-L-threonine
detemir:………… N6.B29-tetradecanoyl-des-B30-L-threonine
glargine:………... [A21-glycine], B30-yl-L-arginyl-L-arginine
glulisine:………… [B3-lysine, B29-glutamic acid]
lispro:…………… [B28-L-lysine, B29-L-proline]

21. https://www. sciencedirect

22. General policy for glycosylated substances
For groups of glycoproteins/glycopeptides identified with a stem (such as -poetin for erythropoetins,
-cog for blood coagulation factors, -ase for enzymes…):
differences in amino acid sequence in the same stem are indicated by using a random prefix (e.g. rizolipase (22), burlulipase (107))
glycosylation is indicated by a Greek letter1 spelt in full and added as a second word to the name. The Greek letters are used in the Greek alphabetical order starting from “alfa” (e.g. epoetin alfa (66), eptacog alfa (activated), aglucosidase alfa (91), epoetin beta (62)).

23. For -mab and -cept:
Although most monoclonal antibodies (-mab) and receptor molecules (-cept) are glycosylated, the first INN application does not have the Greek letter (note however that it is considered “alfa”, despite not having “alfa” in its INN).
If an INN application is received for a -mab or for a -cept with the same amino acid sequence as an existing one, but with differences in the glycosylation pattern requiring a new INN (eg. glycoengineering or having a cell-type glycosylation profile different from the existing application), the INN for the later application will be the existing INN, but with a terminal Greek letter, starting from “beta”.
e.g.
-cog
Nonacog beta pegol
-ase
Vestronidase Alfa-vjbk

24. Vestronidase Alfa-vjbk

25. General policy for pegylated substances
Two different approaches have been used for pegylated substances:
• a single-word scheme with the prefix peg- (e.g. peginterferon alfa-2a (84), pegaldesleukin (74));
• a two-word scheme with the first word representing the biological substance and the second word pegol.
To avoid over-long INN, the two-word scheme has been preferred for names with long stems (e.g. alacizumab pegol (98), calaspargase pegol (105)).

26. PEGylation
PEGylation (often styled pegylation) is the process of both covalent and non-covalent attachment or amalgamation of polyethylene glycol (PEG, in pharmacy called macrogol) polymer chains to molecules and macrostructures, such as a drug, therapeutic protein or vesicle, which is then described as PEGylated (pegylated).
PEGylation is the process of attaching the strands of the polymer PEG to molecules, most typically peptides, proteins, and antibody fragments, that can improve the safety and efficiency of many therapeutics.[6] It produces alterations in the physiochemical properties including changes in conformation, electrostatic binding, hydrophobicity etc. These physical and chemical changes increase systemic retention of the therapeutic agent. Also, it can influence the binding affinity of the therapeutic moiety to the cell receptors and can alter the absorption and distribution patterns.

27. https://en.wikipedia.org/wiki/PEGylation

28. In a few cases, a fantasy prefix has been added to an existing peg- INN to accommodate a new INN request for a similar substance. This has the effect of changing the peg- from a prefix to an infix
(e.g. peginterferon alfa-2b (84) and cepeginterferon alfa-2b (105); pegfilgrastim (86) and empegfilgrastim (107)).
e.g.
Nonacog beta pegol
Elapegademase-lvlr

29. General policy for substances for gene therapy
In 2005, a two-word nomenclature scheme for substances for gene therapy was formally adopted by the members of the INN Expert Group designated to deal with the selection of nonproprietary names.
The 2016 updated scheme for substances for gene therapy using vectors based on recombinant nucleic acid sequences (DNA vectors, e.g. plasmid DNA, naked or complexed), genetically modified micro-organisms (bacterial vectors) or viruses (replication defective, replication competent or replication conditional viral vectors) is shown the next slide.

31. e.g.
Onasemnogene abeparvovec ……………… Onasemno-gene / abe-parvo-vec
Onasemnogene abeparvovec is used to treat spinal muscular atrophy linked to a mutation in the survival motor neuron 1 (SMN1) gene,[8] a genetic disorder diagnosed predominantly in young children that causes progressive loss of muscle function and frequently death.
Voretigene Neparvovec ……………………… Voreti-gene / Ne-parvo-vec
Voretigene neparvovec is an AAV2 vector containing human RPE65 cDNA with a modified Kozak sequence. The virus is grown in HEK 293 cells and purified for administration.

32. General policy for substances for cell therapy
Substances for cell therapy are given a one-word name. Table 3 shows the nomenclature scheme to name all non-genetically modified substances for cell therapy,

34. e.g.
Tisagenlecleucel ………………… Tisagenlec-leu-cel
is a treatment for B-cell acute lymphoblastic leukemia (ALL) which uses the body's own T cells to fight cancer ……(CD19-directed CAR T therapy)

35. General policy for substances for cell-based gene therapy
A two-word name is given to substances for cell-based gene therapy, in which the first word refers to the gene component and the second word refers to the cell component.
The first word is named in the same way as the first word for substances for gene therapy.

36. Nomenclature scheme for genetically modified substances for cell-based therapy

37. e.g.
Axicabtagene Ciloleucel ……………………. Axi-cabta-gene / Cilo-leu-cel
is a treatment for large B-cell lymphoma that has failed conventional treatment.[1] T cells are removed from a person with lymphoma and genetically engineered to produce a specific T-cell receptor. The resulting chimeric antigen receptor T cells or "CAR-Ts" that react to the cancer are then given back to the person to populate the bone marrow.[2] Axicabtagene treatment carries a risk for cytokine release syndrome (CRS) and neurological toxicities.
The T-cells are engineered to target CD19 receptors on the cancerous B cells.

38. https://www. genengnews

39. General policy for substances for virus-based therapy
Substances for virus-based therapy are those for which the virus itself is acting as a therapeutic agent. This is distinct from virus-based gene therapy in which the virus is acting as a carrier of a therapeutic gene. In some cases, the virus may be genetically modified to enhance the therapeutic effect of the virus.
To date, the only virus-based therapies that have been named are oncolytic viruses whereby the virus is used to target and destroy cancer cells.
In the event that a virus-based therapy such as an oncolytic virus is genetically modified to express a therapeutic gene, the virus-based gene therapy nomenclature scheme should be used.

40. Nomenclature scheme for substances for virus-based therapy

41. General policy for monoclonal antibodies
An antibody is a protein used by the immune system to identify and neutralize foreign objects like bacteria and viruses. Each antibody recognizes a specific antigen unique to its target.
Monoclonal antibodies (mAb) are antibodies that are identical because they were produced by one type of immune cell, all clones of a single parent cell.
Polyclonal antibodies are antibodies that are derived from different cell lines.

42. Monoclonal antibodies (mAb) are antibodies that are identical because they were produced by one type of immune cell, all clones of a single parent cell.
Given (almost) any substance, it is possible to create monoclonal antibodies that specifically bind to that substance; they can then serve to detect or purify that substance.
This has become an important tool in biochemistry, molecular biology and medicine.

43. Nomenclature:
Stem
All monoclonal antibody names end with the stem -mab
Substem for origin/source
The substem preceding the stem denoted the animal from which the antibody was obtained
Substem for target
The substem preceding the source of the antibody refers to the medicine's target

44. Prefix
The prefix carries no special meaning. It should be unique for each medicine and contribute to a well-sounding name
This means that antibodies with the same source and target substems are only distinguished by their prefix. Even antibodies targeting exactly the same structure are differently prefixed, such as the adalimumab and golimumab, both of which are TNF inhibitors but differ in their chemical structure

46. Nomenclature scheme for monoclonal antibodies (mAb)

47. Second word
If the monoclonal antibody is conjugated to another protein or to a chemical (e.g. chelator), identification of the conjugate is accomplished by use of a separate, second word or acceptable chemical designation. For mAbs conjugated to a toxin, the suffix -tox is used in the second word.
If the monoclonal antibody is radiolabelled, the radioisotope is listed first in the INN, e.g. technetium (99mTc) nofetumomab merpentan (81).
Pegylation
For pegylated monoclonal antibodies see item 2.4: General policy for pegylated substances.
Glycosylation
For glycosylated monoclonal antibodies see item 2.2: General policy for glycosylated substances.

48. Nomenclature

49. Examples Olaratumab : is an antineoplastic.
Its name is composed of the components olara-t-u-mab.
This shows that the drug is a human monoclonal antibody acting against tumors.
Benralizumab :
a drug designed for the treatment of asthma
, has the components benra-li-zu-mab, marking it as a humanized antibody acting on the immune system

50. General policy for blood products
INN are not assigned to natural human blood products
Many natural blood products have well-established names; the recombinant version should have a distinctive name reflecting as much as possible the established name used in the field.
It is essential to add "activated" to the name of the blood product when this is presented for therapeutic use in its activated form.

51. General policy for vaccines
Vaccines are traditionally considered to be medicinal substances used to stimulate an individual’s immune system into providing protection against a particular infectious disease. Traditional vaccines consist of whole killed pathogens, live attenuated pathogens, subunits (antigens) derived from pathogens, or inactivated pathogenic toxins.
At present, vaccines are not included within the INN system, with names being assigned through recommendations of the Expert Committee on Biological Standardization and through pharmacopoeial monographs.

52. NAMES FOR SALTS, RADICALS AND GROUPS

53. As a general rule, since 1975 INNs are selected for the active moiety of pharmaceutical substances. In the case of INNs of salts and esters it is left to the user to devise their names from the INN in conformity with normal chemical practice. Separate names for salts and esters derived from this procedure are not published.
The same approach should be followed in the case of combination products. In all those situations, names are referred to as International Nonproprietary Name Modified INNM.
Some of the radicals and groups involved are, however, of such complexity that, shorter nonproprietary names are selected for these inactive moieties, and published in proposed lists under the title "names for radicals and groups". If a "radical and group name" is used in conjunction with an INN, it is also referred to as an INNM.
In some cases, a name of an INN Radical describes more than one substituent, e.g. (names in Latin) acefuras, aceponas, enbutas, stinopras,… Alphabetical list of currently used names for radicals and groups is given in the main part of the document, while the names of elements and chemical groups that were published together with INNs are given in Annex 1.

54. Modified INNs (INNMs)
In principle, INNs are selected only for the active part of the molecule, which is usually the base, acid or
alcohol. In some cases, however, the active molecules need to be expanded for various reasons, such as
formulation purposes, bioavailability or absorption rate. In 1975 the experts designated for the selection
of INN decided to adopt a new policy for naming such molecules. In future, names for different salts or
esters of the same active substance should differ only with regard to the inactive moiety of the molecule.
For example, oxacillin and ibufenac are INNs and their salts are named oxacillin sodium and ibufenac
sodium. The latter are called modified INNs (INNMs).
Before the existence of this rule, some INNs were published for salts. In such cases, the term "modified
INN" may also be used for a base or acid. For example, levothyroxine sodium was published as an INN and levothyroxine may thus be referred to as an INNM.

55. Mirogabalin besilate

56. Omadacycline Tosylate

57. Olmesartan medoxomil