Hormones and compounds acting within the endocrinous system, if they were
not refered elsewhere
1. Peptides and proteins
2. Compounds derived from a single amino acid
3. Steroids
3.1. Corticoids
3.1.1. Mineralocorticoids
3.1.2. Glucocorticoids
3.2. Sex hormones
3.2.1. Androgens
3.2.2. Estrogens
3.2.3. Gestagens
4. Prostaglandins
© Oldřich Farsa 2017
Classification of hormones of peptide and protein structure
1.1 Liberins a statins („releasing“&“inhibiting“)
1.2.Soma(to)tropin
1.3 Oxytocin, vasopressin and their analogues
1.4 Insulines, glucagon and GLP-1 analogues
1.5 Calcitonin
2. Blood factors of erythropoietine type
3. Colony stimulating factors
One- and three-letter symbols of L--amino acid rests
One-letter Three-letter
A Ala alanine
B Asx asparaginic acid or asparagine
C Cys cysteine
D Asp asparaginic acid
E Glu glutamic acid
F Phe phenylalanine
G Gly glycine
H His histidine
I Ile isoleucine
K Lys lysine
L Leu leucine
M Met methionine
N Asn asparagine
P Pro proline
Q Gln glutamine
R Arg arginine
S Ser serine
T Thr threonine
U Sec selenocysteine
V Val valine
W Trp tryptofane
X Xaa unknown or „other“ amino acid
Y Tyr thyrosine
Z Glx glutamic acid or glutamine (or compounds such
as 4-carboxyglutamic acid 5-oxoproline)
1. Hormones
1.1 Liberins and statins („releasing“ & „inhibiting“)
Gonadorelin (GnRH = LHRH) and its analogues
●hormone of hypothalamus
●stimulates releasing of folicules stimulating hormone (FSH) and luteinizing hormone (LH)
from pituitary gland; GnRH receptors also in various non-reproductive tissues
gonadorelin acetate Gonadorelini acetas EP
buserelin Buserelinum EP
goserelin Goserelinum EP
Gonadorelin agonists
Gonadorelin and its analogues
Agonists
leuprorelin (syn. leuprolide) Leuprorelinum EP
Eligard ®
●
longer-term application lowers testosterone levels  treatment of prostate cancer
 treatment of sexual deviations
OH
OH
OH
O
OH
O
NN
H
O
O
O N
H
O
NH2
NH
O
NH
NH NH2
CH3
CH3
N
H
N
N
H
N
H
N
H
N
H
N
H
N
H
O
O
OH
O
O
O
O
OH
N
H
O
OH
OHO
OH
OH
Gonadorelin and its analogues
Agonists
Short- and long term action of gonadorelin agonists
●long term action leads to receptors internalisation and stopping of the effect (due to
decreasing LH and FSH levels and thus also levels of sexual hormones)
Gonadorelin analogues
Gonadorelin antagonists
. CH3
COOH
. CH3
COOH
N
H O
N
H
Cl
N
H
O
N
H
OH
N
H
O
OH
N
H
O
N
H
O
CH3
CH3
N
H O
N
O
N
H
O
CH3
NH2
N
O
CH3
N
NH N
H
CH3
CH3
N
N
H
N
H
CH3
CH3
OO
ganirelix
N
H O
N
H
O
Cl
N
H
O
N
H O
OH
N
H O
OH
N
H
O
NH
N
H
O
CH3
CH3
N
H
NH2
NH
N
H
O
N
O
N
H
O
CH3
NH2
O NH2
N
O
CH3
cetrorelix
Gonadorelin and its analogues
●preparation: chemical synthesis
●usage: assisted reproduction, treatment of prostate cancer, sexual deviation ...
●
advantages of analogues: significantly higher stability  longer elimination half-time 
 possibility of application in markedly longer intervals; a single injection of an agonist can
replace a continuous infusion of gonadorelin
Structure – activity relationships (SAR)
●replacement of Gly in position 6 with a more bulky amino acid leads to stability increase
●the sequence of the first three amino acids is needed for receptor binding and is kept in
agonists
● antagonists have Trp in position 3 replaced with an non-physiologic amino acid, they bind
to GnRH and avoid its action on receptors
Corticotropin and its analogues
Corticotropin = Adrenocorticotrophic hormone (ACTH); an anterior pituitary hormone that stimulates the
adrenal cortex and
its production of both gluco- and mineralocorticoids and growth of adrenal glands
●polypeptide of 39 amino acids; N-terminal 24 identical in all species
●N-terminal 24 AA are responsible for biologic activity; C-terminal 15 AA for immunospecificity
corticotropin
tetracosactide
syn. cosyntropin [USAN]
Tetracosactidum EP
Synacten
SynVL
●compound used as a standard
for determination of
tetracosactide by mass
spectrometry
Usage of corticotropin and tetracosactide
●diagnosis of adrenal glands function
●substitution treatment in lack of glucocorticoids
●substitution of depot administration of glucocorticoids in a long-term treatment
N
N
N
N
H
N
N
HOH
N
H
N
H
N
H
N
H
N
H
NH
OH
O
NH2
O
OH
O
S
CH3
O
OHO
O
O
N
H
N
H
N
H
O
NH
NH2 NH
O
O
ONH
O
NH2
O
NH
CH3
CH3
O
NH
N
H
O
N
H
N
H
N
H
NH2
O
NH2
O
NH
NH2 NH
O
NH
NH2
NH
O
O
N
H
N
H
N
H
CH3 CH3
O
O
NH2
CH3CH3
O
NH
OH
O
OOH
tetracosactide
●used since 1961
●prepared by synthesis
●misused for doping in sport
Protirelin – synthetic thyreotropin-releasing hormone (TRH)
●a hormone sythetized in paraventricular nucleus of hypothalamus, stimulating release of
thyreotropin and prolactin from the anterior pituitary gland
●also neurotransmitter in CNS, takes part in food intake regulation, control of energy
metabolism etc.
N
O
NH2
O
N
H
N
O NH
N
H
O
protirelin
5-oxoprolyl-histidyl-prolinamide
Protirelinum EP
●structure elucidated 1969, used approx. 1976 – 1991, then abandoned
●administered p.o.
●used as cognitive functions enhacer for treatment of post-traumatic conditions in injuries
of brain and spinal cord and of neurodegeneration diseases (Alzheimer, Parkinson,
motoric neuronal disease etc.)
Metabolism of TRH and its regulation
Somatostatin
●cyclic tetradecapeptide formed namely in hypothalamus, but also in peripheral nervous
●system, the gut, and other organs
●inhibits pituitary growth hormone (somatotropin) release and probably also release of TRH,
prolactin,insulin and glucagon
●has impact to functions of kidneys, pancreas and GIT
●also acts as neurotransmitter in CNS („neuropeptide“)
NH
N
H
NH
O
O
N
H
N
H
O
O
N
H
N
H
O
CH3
OH
NH2
O
N
H
N
H
O
O
NH2
O
N
H
N
H
O
CH3OH
O
N
H
S
NH2
N
H
O
OH
S
O
N
H
OH O
O
CH3
NH2
somatostatin
Somatostatinum EP
Somatostatin Eumedica
inf.
●prepared by synthesis
●treatment of acromegaly
1.2 Soma(to)tropin
= growth hormone (GH)
●peptide consisted of 191 AA secreted from anterior pituitary gland
●stimilates mitosis, growth and differentiation of cells of some tissues
●influences expression of genes and metabolism
●sequence of AA known since 1972, nucleotide sequence of the encoding gene since 1977
somatropin
Somatropinum EP
●human, prepared by recombinant technology, used since 1985
●substitution treatment of natural GH deficiency
Genotropin ® , Humatrope ® , Nutropinaq ® , Omnitrope ® ...
tertiary structure of porcine GH
1 MATGSRTSLL LAFGLLCLPW LQEGSAFPTI PLSRLFDNAM LRAHRLHQLA FDTYQEFEEA YIPKEQKYSF LQNPQTSLCF SESIPTPSNR EETQQKSNLE 100
101 LLRISLLLIQ SWLEPVQFLR SVFANSLVYG ASDSNVYDLL KDLEEGIQTL MGRLEDGSPR TGQIFKQTYS KFDTNSHNDD ALLKNYGLLY CFRKDMDKVE 200
201 TFLRIVQCRS VEGSCGF
Primary structure of human somatropin
Śomatropin (GH) analogues
pegvisomant
●analogue – antagonist of human GH, in which 9 AA are changed, which enables it to block
binding of native GH to its receptor by means of preventing receptor dimerisation
●pegylation is performed on 4 – 5 sites randomly selected from Phe1
and various 8 Lys residues
●prepared by the recombinant technology followed by a controlled reaction with oxiran
(polyadition) which results to covalent binding of 4 – 5 polyoxoethylene chains of Mr
 500
●pegylation lowers antigenicity and prolongs the biologic half-time
●using: treatment of acromegaly
1.3 Oxytocin, vasopressins and their analogues
Vasotocin
= fylogenetic precursor of oxytocine and vasopressins in organisms lower than mammals
●prepared by synthesis
●used for triggering of the birth and enhancing of uterine contractions
Oxytocinum EP; Oxytocin Ferring-Léčiva ® inj. sol.
Oxytocin
● a cyclic nonapeptide released from the posterior pituitary gland (neurohypophysis)
●acts on smooth muscle cells, such as causing uterine contractions and milk ejection
N
O
N
H
O
NH
S
O
S
NHO
NH
N
H
O
NH2
O
NH2
NH2
O
N
H
N
H
O
NH2
NH
O
NH
NH2
O
O
CH3
CH3
OH
H-Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Arg-Gly-NH2
Vasopressin(s)
=antidiuretic hormone(s) (ADH)
●octapeptides released from the neurohypophysis of all vertebrates (precursor synthetized in
hypothalamus)
●control body water content (regulation of kidneys, lungs etc.)
●potential neurotransmitters
●semi-synthetic derivatives used predominantly
N
O
N
H
O
NH
S
O
S
NHO
NH
N
H
O
NH2
O
NH2
NH2
O
N
H
N
H
O
NH2
NH
O
NH
NH2
O
O
OH
N
O
N
H
O
NH
S
O
S
NHO
NH
O
NH2
O
NH2
NH2
O
NH2
N
H
N
H
O
O
NH
NH2
O
O
OH
arginine-vasopressin
argipressin
●predominant form of mammalian ADH
lysine-vasopressin
lypressin
●Suidae family only
●treatment of diabetes insipidus and low blood pressure
Vasopressin analogues
Desmopressin
Desmopressinum EP
●cyclic pseudononapeptide
●prepared by synthesis
●antidiuretic (enuresis nocturna, ...)
Vaspressin analogues
Felypressin
Felypressinum EP
●vasoconstrictor with reduced antidiuretic activity
T
T
Terlipressin
NH2Pro
PheGly TyrCys
LysGln
GlyNH2 Gly
Asn Cys Gly
H-Gly-Gly-Gly-Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Lys-Gly-NH2
●vasoconstrictor, treatment of variceal bleeding, circulation and septic shock
Glypressin ®
inj., Remestyp ®
inj.
Calcitonin
●released from thyroidal C-cells ( = parafolicular cells – Baber 1876), in lower
vertebrates from ultimobranchial bodies, originated from 5th
branchial fissure
●peptide from 32 amino acid residues (salmon's – Onchorhyncus kisutch; human has
139 AA)
●receptors on osteoclasts (also in kidneys and brain)
●
 excretion of Ca2+
from the bone (  calcaemia)
●
 osteoclasts formation
●used together with Ca2+
for treatment of osteoporosis
Calcitonin
N
N
N
H
N
H O
NH2O
O
NH
N
H
N
H
N
H
N
H
S
S
N
H
NH2
O
O O
O
OH
O
OH
O
O
NH2
OH
N
H
N
HO
O
N
H
O
N
H
O
NH2
O N
H NH
O
OH
ONH
NH2
O
O
NH
O
N
H
O
N
H
N
H O
N
NH
O
NH2
O
N
H
OH
N
H
O
OH
O
O
N
H
O
NH
NH
NH2
O N
H
NH
OH
N
H
N
H
N
H
NH2
O
O
OH
O
O
OH
N
H
N
HO
O
OH
O
ONH2
OH
Calcitoninum salmonis EP = calcitonin salmon (synthetic; AA sequence
coresponds with salmon hormon)
Miacalcic®
inj., nasal; Osteodon®
; Tonocalcin®
2. Blood factors of erythropoetine type
erythropoietin
= glycosylated protein from 165 AA
Erythropoietini solutio concentrata EP
= a solution containing a group of closely related glycoproteins, which are not to distinguish
from the natural human erythopoietin (urine erythropoietin) from the point of view of 165
amino acids sequence and their average profile of glycosylation
●naturally released fromkidneys of adults and in liver of foetus
●stimulates stemcells of bone marrow to proliferation and differentiation
●produced in vitro in rodent cell lines by a method based on the recombinant DNA
technology
●treatment of haematopoietic disorders, misused for doping
Mr
about 30 600
3. Colony stimulating factors
molgramostim
= a factor stimulating granulocytes and macrophages colonies released from various kinds
of blood cells
●not glycosylated
●stimulates differentiation and proliferation of leukocyte pluripotent stem cells into matured
granulocytes and macrophages
●production by a recombinant technology using bacteria as host cells
● treatment of leukopenia in cancer chemotherapy or HIV infections
Filgrastim and pegfilgrastim
Filgrastim = human granulocytes colony-stimulating factor (G-CSF); glycosylated, 174 AA
Sequence of filgrastim precursor
●
treatment of neutropenia in cancer chemotheapy and in AIDS
Pegfilgrastim has covalently attached PEG chain of Mr
cca 20 000 on N-terminus
●longer elimination half-time
●recombinant and semi-synthetic production
2. Hormones derived from a single amino acid
Thyroid hormones
O
NH2
O OH
OH
I
I
R
I
R = -H
liothyronine, syn. L-3,5,3´-trijodothyronine, T3
R = -I
levothyroxine, syn. L-3,5,3´,5´-tetrajodothyronine, T4
Levothyroxinum natricum hydricum PhEur
●Thyroid hypofunction caused by lack of thyroxine
Drugs used in thyroid dysfunctions
Thyrotropics
KI
potassium iodide
●prevention of thyroid hypo-function due to lack of iodine (goitre, cretinism) – additive to
NaCl
●prevention of striking by radioactive I2
in a potential nuclear power plant accident: JODID
DRASELNÝ 65 VULM
Drugs used in thyroid dysfunctions
Thyrostatics
KClO4
potassium perchlorate
Kalii perchloras PhEur
Thiouracil derivatives
NH
N
H
SR
O
R = -CH3
methylthiouracil
R = -C3
H7
propylthiouracil
Propylthiouracilum PhEur
2-mercaptoimidazole derivatives
N
N
SH
CH3 N
N
S
CH3
O
CH3
O N
N
SH
CH3
O
CH3
OH
thiamazol
syn. methimazol [USAN, BAN]
carbimazole
●Mode of action of both thiouracils and mercaptoimidazoles: inhibition of thyroidal
peroxidase   2 I
I2
  embedding of I2
into tyrosyl rests  T3 and T4 formation
●common structural fragment: thiourea
„Radiothyrostatics“ and thyroid diagnostics
●
Na131
I for radio-therapeutic purposes: treatment of thyroid
carcinoma including metastases, diagnose of cancers
●123
I,99
Tc: diagnoses of benign conditions
3. Steroid hormones
13
149
810
17
12
11
15
16
75
6
20
CH3
18
CH3
191
23
22
4
CH3
21
24
2
3
H
H
H
H
25
CH3
27
CH3
26
cholestane – the largest steroid skeleton of the human organism
3.1. Corticoids = adrenal cortex hormones
3.1.1. Mineralocorticoids
●secreted from Zona glomerulosa of supra-renal glands cortex13
149
810
17
12
11
15
16
7
5
6
CH3
18
CH3
19
1
4
2
3
H
H
H
20 CH3
21
H
pregnane
aldosterone
●
control of ratio Na+
/K+
and water distribution in tissues
●
 tubular back resorption of Na+
  water excretion by kidneys and  excretion of both K+
and H+
by change for Na+
●secretion of aldosterone is controlled by angiotensin II and probably also by osmotic and
volume receptors
●„adversary“: atrial natriuretic factor (ATF); a polypeptide formed in the heart
O
CH3
O
OH OHO
O
CH3
OH
OHO
H
O
OH2
- H2
O
(cyclo)hemiacetal form
Further mineralocorticoids
H
O
CH3
H
CH3
H
H
O
OH
desoxycortone
syn. desoxycorticosterone
[USAN]
H
OH
O
OH
CH3
H
OH
F
H
O
CH3
fludrocortisone
H
OH
O
OH
CH3
H
OH
F
H
O
CH3
CH3
9a-fluoro-2a-methylcortisol
●natural
●biosynt. intermediate of
glucocorticoide corticosterone
Desoxycortoni acetas PhEur
●subst. treatment in
supra-renal insufficiency
Astonin-H®
Structure-activity relationships (SAR)
●introduction of F into pos. 9 strengthens mineralocorticoid activity, -CH3
in pos. 2 also
and more  9a-fluoro-2-methylcortisol is 30x more active than aldosterone
O
CH3
O
OH OHO
O
O
CH3
CH3
O
S
CH3
O
OH
O
CH3
CH3
O
OH
H2O
- CH3COSH
spironolactone
prodrug of canrenoic acid
for oral application
Verospiron®
tbl.
canrenoic acid
real active compound
Aldactone® inj. – K+
salt for
parent. application (kalii
canrenoas)
Aldosterone antagonists = „potassium conserving“ diuretics
inhibit reabsorbtion of Na+
in distal tubule; simultaneously retention of K+
occurs
aldosterone
13
149
810
17
12
11
15
16
7
5
6
CH3
18
CH3
19
1
4
2
3
H
H
H
20 CH3
21
H
pregnane
3.1.2. Glucocorticoids
●secreted from Zona fasciculata of supra-renal glands cortex
H
OH CH3
H
OH
O
OH
H
O
CH3
H
O
CH3
H
OH
O
OH
H
O
CH3
H
H
OH CH3
H
O
OH
H
O
CH3
H
hydrocortisone, syn. cortisolcortisonecorticosterone
●first isolated by Reichstein 1936 ●first isolated
simultaneously by
Reichstein and Kendall
(1939)
●first used by Hench for
Addison disease and
rheumatism treatment
(1950)
(rel. anti-inflammatory
activity = 1)
Nobel prize for physiology and medicine holders (1950)
Edward C. Kendall Philip S. Hench Tadeus Reichstein
Effects of glucocorticoids
●
 gluconeogenesis from amino acids, which are formed by proteins cleavage; a portion of
glukose stored in glycogen, a portion released into the blood ( „steroid diabetes“)
●block all inflammatory processes
●
cortisol excretion  in stress conditions as a protective reaction („energy emergency“)
Target structures – sites of action:
●
steroid receptor is in cell nucleus, stimulation   neo-formation of enzymes taking part in
proteins metabolism (e.g. tyrosinaminotransferase) and sugars e.g. pyruvatecarboxylase)
●binding site also on GABA-receptor
●etc.
Usage: anti-inflammatory drugs, anti-rheumatics, anti-asthmatics, immunosuppressants,
treatment of multiple sclerosis, lupus erythematodes, substitution therapy (Addison´s
disease) etc.
Adverse effects: Cushing syndrome
The role of glucocorticoids in metabolism of eicosanoids
COOH
C
H2
C
H2
O R1
OR2
O
O
O
P O
O
OH
N
+
CH3
CH3
CH3
OHR2
O
COOHO
O
OOH
COOH
OOH
arachidonic acid
=
PG G2
PG H2
TX A2
trombocytes PG D2 PG E2
PG F2
all the cells
PG I2 = prostacyklin
endothelium cells LT A4
LT C4
LT D4
LT E4
LT B4
cyclooxygenases (COX1 + COX2) lipoxygenase
phspholipase A2inhibitors of
prostaglandins
sythesis =
= "weak"
analgesics +
+ NSAIDs
glucocorticoids
lipoxygenase inhibitors
arachidonic
acid
tromboxan synthase prostacyklin synthase
isomerases
cyklooxygenases
5-hydroperoxy-6-trans-8,11,14-cis-eikosatetraenoic acid
(5-HPETE)
glucocorticoids
Structure-activity relationships (SAR)
●
the “upper” -side of the skeleton is more important for the interaction with the steroid
receptor
●ketonic group in ring A conjugated with double bond is necessary for the activity
●
-ketol group in position 17 also
●an oxygenous group in pos. 11 also
●
hydroxyl in pos. 17 increases the activity
Synthetic changes for more suitable profile of activity
●
further double bond in pos. resulted to  anti-inflammatory activity 4x, mineralocorticoid one 
about 2/3 ( prednisolone, prednisone)
●
fluorination in pos. 9  preferably mineralocorticoid activity, glucocorticoid effect also
growths; it  with electronegativity and  with bulkiness of a substituent (for 9-Cl 5x greater);
this effect is not caused by simple  of acidity 11-OH as a result of elektronacceptor effect of
the substituent in pos. 9, because affinity of 9-Cl a 9-F derivatives to the receptor does
not differ
●
fluorination in pos. 6 has similar, but weaker impact; methylation in this position  glucocort.
activity 10x, the mineralocort. one is mildly lowered
●
9-methylation  further glucocort. activity; mineralocort. activity is almost lost
(fluocortolone, dexamethasone, betamethasone...); hydroxylation has the same effect
(triamcinolone, fluocinolone)
Glucocorticoids – steroidal anti-inflammatory drugs
H
O
2
1 CH3
H 11
OH
CH3
H
OH
O
OH
H
O
CH3
H
O
CH3
H
OH
O
OH
prednisolone prednisone
●rel. activity = 4
H
16
H
OH
OH
O
OH
CH3H
OH
9
F
H
O
CH3
H
16
H
CH3
O
OH
CH3H
OH
H
6O
CH3
F
fluocortolone
●5
triamcinolone
●6
Glucocorticoids – steroidal anti-inflammatory drugs
H
16
H
CH3
OH
O
OH
CH3H
OH
9
F
H
O
CH3
H
16
H
CH3
OH
O
OH
CH3H
OH
9
F
H
O
CH3
dexamethasone
●30
betamethasone
●30
Glucocorticoids – steroidal anti-inflammatory drugs
Glucocortikoids – antialergics, antiasthmatics and their prodrugs
O
H
OH
H
H
H
CH3
HF
O
CH3
F
CH3
S
F
O
R
R = H- fluticasone
R = CH3CH2CO- fluticasone propionate
Seretide(R)
Inhaler (+ salmeterol)
R = fluticasone furoate
Avamys(R)
27,5 mg susp. - nasal spray
O
O
O
H
H
O
CH3 Cl
H
OH
H
CH3
CH3
Cl
O
R
R = H- mometasone
R = mometasone furoate
Asmanex(R)
200 mg inh. plv.
O
O
Topically administered steroid anti-inflammatory drugs
●
 lipofillicity desirable  prodrugs of ester or acetal type
CH3
H
O
CH3
F
OH
CH3
O
OH
doximethason
H
H
CH3
OH
O
O
O
CH
CH3
CH3
CH3
H
OH
F
HF
O
CH3
flumethasone pivalate
Topically administered steroid anti-inflammatory drugs (continued)
HF
H H
H
O
CH3
CH3
O
O
OH
CH3
H
OH
FCH3
O
fluocinolone acetonide
H
H
CH3
O
O
O
CH3
CH3
H
OH
HF
O
CH3
fluorocortin butylester
●rapidly hydrolysed to inactive free
carboxylic acid by esterases of the skin 
no system activity
CH3
O
O O
O
CH3
OH
CH3
O
O
O
CH3
prednicarbate
●
fast hydrolysis and further inactivation by biotransformation  minimal systemic effect
Topically administered steroid anti-inflammatory drugs (continued)
Prodrugs of glucocorticoids
●esters with shorter alkanoic acids (acetic, propionic, valeric, caproic, pivaloic) at C17
and/or C21 for topical skin administration
●monoesters with polyhydric acids (succinic, H3
PO4
) usually at C21 for injection
administration in the form of a salt
●acetals bridging C16 and C17
H
H
OH
OH
O
OH CH3H
OH
F
H
O
CH3
+ CH3 CH3
O H+
H
H
O
OO
OH
CH3
H
OH
F
H
O
CH3
CH3
CH3
triamcinolone triamcinolone acetonide
+ H2O
Example of preparation of an acetal prodrug
3.2. Sex hornomes
3.2.1. Androgens13
149
810
17
12
11
15
16
7
5
6
CH3
18
CH3
19
1
4
2
3
H
H
H
androstane
CH3
CH3
H
H
H
OH
O
CH3
CH3
H
H
H
O
OH
androsterone testosterone
●a metabolite of testosterone
●
1st
isolated male sex hormone
(Butenandt 1931)
●1935
●10x more efficient
●T1/2
= 10 min  ester prodrugs needed
●p.o. inactive due to high first-pass effect
Androgens – therapeutics in use
17
CH3
CH3
H
H
H
O
O
R
O
17
CH3
CH3
1
H
H
H
OH
O
CH3
R = -C2
H5
testosterone propionate
R = -(CH2
)2
CH(CH3
)2
testosterone isocaproate
R = -C6
H13
testosterone enanthate
etc.
●i.m. administration
mestrenolon
●applicable p.o.
Effects of androgens
●formation of secondary sex signs, spermatogenesis, libido
●
anabolic:  biosynthesis of proteins of the muscle tissue (sex independent)
Usage as therapeutics
●substitution treatment of hypogonadism
●breast cancer treatment
Anabolics
●
analogues of testosterone, in which anabolic effect is  and androgenic one is  by changes
of the structure
●impact also metabolism of carbohydrates and minerals
●
androgenic effect in part kept  virilization in women (1st
sign: change of position of voice)
●
therapeutic indications: anorexia, serious protein deficiency
CH3
O
O
O
1
CH3
CH3
CH3
H
5
O
H
H
CH3
H
H
O
O
CH3
methenolone acetate
19-nortestosterone decanoate
nandrolone decanoate
Nandroloni decanoas PhEur
Anabolics
H
4
Cl
O
CH3
H
CH3
H
H
O
CH3
O
clostebol acetate
syn. turinabol
3.2.2. Oestrogens
13
149
810
17
12
11
15
16
7
5
6
CH3
18
H1
4
2
3
H
H
H
estrane
H
CH3
O
H
H
OH
H
CH3
17
H
OH
16
H
OH
H
H
OH
H
CH3
H
OH
H
H
OH
estrone
●1st isolated oestrogen
(Doisy and Butenandt
1929)
●structure elucidated 1932
(Butenandt)
●30% activity
estriol
●metab. product
●10% activity
estradiol
●„true“ hormon
●100% activity
Oestrogens
Effects and usage
●development and keeping of female sex signs
●
also extra-genital lipid-anabolic effect  development of subcutaneous fat tissue
●substitution therapy in hypogonadism
●prevention and treatment of osteoporosis in climacteric women
●lactation termination
●treatment of prostate cancer
●a component of hormonal contraception
SAR
●
among natural ostrogens, only little active estriol is applicable p.o.  changes of the
structure or estradiol in transdermal therapeutic systems (TTS)
●
ethinyl to 17 position  good p.o. activity; only slow degradation in liver
●T1/2
of estradiol in parenteral application only 50 min  ester prodrugs
●also stilbene derivatives; today only for treatment of prostate cancer; they damage the
tissue with oestrogen receptors
●fytooestrogens: „non-hormonal“ compounds of plant origin, used for relief of
climacteric problems; some of them are also stilbene derivatives (carcinogenicity)
Orally active oestrogens
H
CH3
OH
H
H
OH
CH
H
CH3
OH
H
H
O
CH
CH3
ethinylestradiol mestranol
Examples of ester prodrugs of oestrogens pro depot i.m. application
H
CH3
H
OH
HH
O
O
H
CH3
H
O
HH
OH
CH3
O
estradiol-3-benzoate
estradiol-17-valerate
●oil solutions for i.m. injections
O
O
H
H
H
H
H
H
H
H
H
H
H
H
HH
H
H
H
H
H
H
H
H
H H
O
O H
H
H
H
H
H
H
H
H
H
HH
H
H
H
H
H
H
H
H
Steroid and non-steroid oestrogens
●the distance between -OH groups is essetial for interaction with oestrogen receptor
estradiol
distance between -OH(C3) a
-OH(C17) 11.109 Å
diethylstilbestrol
distence of phenolic -OH 12.342 Å
Non-steroid oestrogens
CH3
OH
CH3
OH
CH3
CH3
OH
OH
OH4'
O
OH
7
OH
O
diethylstilbestrol
●
a component of the 1st
generation contraceptives
●today prostate cancer
treatment only
●toxic, carcinogenic, damages
the tissue containing oestrogen
receptors, alters expression of
many genes,  incidence of
uterus cancer even in low
doses, genetic harm is
transferred to the offspring
●„endocrine disruptor“
●model compound for study of
negative oestrogenic effects of
many compounds to the
environment
hexestrol
●lower activity
genistein
●isoflavonoid
●in plants (in the food) in
form of glycosides, which
are cleft by intestinal
microflora, good
absorption
●
prevention of climacteric
problems
●distance 7-OH and 4´-OH
13.161 Å
3.2.3. (Pro)gestagens
13
149
810
17
12
11
15
16
7
5
6
CH3
18
CH3
191
4
2
3
H
H
H
20 CH3
21
H
pregnane
CH3
CH3
H
H
H
CH3
H
O
O
CH3
CH3
HH
H
CH3
O
O
O
CH3
O
4-pregnene-3,20-dion
progesterone
Progesteronum PhEur
●isolated 1934 from yellow bodies of
pregnant sows (female pigs), structure
elucidated by Slotta 1935
●intermediate of corticoids and
androgens biosynthesis
●p.o. little active
●T1/2
= 20 min  i.v. shortly active
17-hydroxyprogesterone hexanoate
●i.m. depot injections
Gestagens
Effects and usage
●progesterone is responsible for control of all the reproduction processes in woman
●keeping of the pregnancy (gestare = lat. carry)
●
synthesised in yellow body in the 2nd
half of the cycle, during pregnancy mostly in
placenta
●therapeutically used together with oestrogens for normalisation of cycle anomalies
●shift of menstruation out of a “unsuitable” time
●with oestrogens in p.o. hormonal contraception
SAR
●usually C=O in position 3, methyl 19, CH3
CO- in pos. 17; although, none of these
fragments is absolutely necessary for gestagene activity
●CH3
CO- in pos. 17 can be repaced with ethinyl without loss of activity
●19-nortestosterone derivatives have high gestagene activity (norethisteron)
●compounds without ketonic group in pos. 3 are also active (lynestrenol)
●
replacement of methyl at C13 (C18 methyl) with ethyl  p.o. activity (norgestrel)
●
introduction of double bond into the ring B to C6 also  p.o. activity (megestrol,
chlormadinon)
●methylation on C6 to -position results also in p.o. aplicable compound ; T1/2
 by
introduction of 17-OH and its esterification (medroxyprogesterone acetate)
P.o. applicable gestagens
17-ethinyl-17-hydroxyderivatives
10
17
CH3
H
H
H
CH
OH
O
CH3
HH
H
CH
OH
H
H
H
CH
OH
O
CH3
norethisterone
●acetate is official
Norethisteroni acetas
PhEur
lynesterol
D-(-)-norgestrel
levonorgestrel
Levonorgestrelum PhEur
P.o. applicable gestagens
Compounds changed in ring B
CH3
CH3
H
H
H
CH3
O
O
O
Cl
O
CH3
6
CH3
CH3
HH
H
CH3
O
O
O
CH3
O
CH3
H
CH3
CH3
H
H
H
CH3
O
O
O
CH3
O
CH3
chlormadinone acetate megestrol acetate
Megestroli acetas PhEur
medroxyprogesterone acetate
Medroxyprogesteroni acetas PhEur
Provera®
Hormonal contraceptives
●gestagen is the main component
●antigonadotropic effect: prevention of ovulation; furthermore prevention of nidation
●
 viscosity of mucus of cervix avoids penetration of spermcells
●
purely gestagen preparations do not prevent ovulation, only  viscosity of cervical mucus,
therefore less reliable
4. Prostaglandins
CH3
20
19
18
17
16
15
14
13
12
H
11
10
9
8
H 7
6
5
4
3
2
1
OH
O
prostanoic acid
●prostanoic acid derivatives
●discovered by Euler 1934, isolated from sperma by
Bergström 1957
●differ one from each other by substitution on
cyclopentane rings and/or by positions and number of
double bondns in side chains
●all natural ones have double bond on C13 and -OH
on C15
●primary prostaglandins: D, E, F
●secondary ones are formed by their dehydratation
and isomerisation
Primary prostaglandins
CH3
H
OH
HOH
O
H
OH
O
CH3
H
OH
HOH
O
H
OH
O
CH3
H
OH
H
HOH
H
OH H
OH
O
PGE1
PGE2
alprostandil
PGF2
dinoprost
Enaprost F ® , Prepidil ® ,
Prostin E2 ®
●induction of birth
Secondary prostaglandins
CH3
H
OH
H
O
H
OH
O
PGA1
CH3
H
OH
OH
O
O
PGB1
CH3
H
OH
OH
O
O
PGC
Effects of prostaglandins
●activities are extensive, complex and not completely elucidated till now
●participate in inflammatory processes, senzitize nociceptors
●PGE affects smooth vascular musculature directly and lowers blood pressure; dilates bronchi
●
PG2 cause bronchoconstriction
●
both PGE2 and PGF2 causes contraction of uterus; birth initiation ( sulproston)
●
PGE acts on the mucous membrane of the stomach as cytoprotective agent ( misoprostol)
Drugs derived from prostaglandins
CH3
S
O O
NH
O
H
H
H
OH
O
H
OH
O
sulproston
CH3
CH3
OH
H
H
OH
O
H
O
O CH3
misoprostol
●initiation of birth ●gastric protectant