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Thyroid function and thyroid drugs

SAR9808 Engineer ofstructure

fee
Dr. Suriyan Thengyai, PhD
School of Pharmacy, WU
suriyan.te@wu.ac.th

Medicinal Chemistry 2 (PHD-332)


Learning Objectives

After this class, the students have to understand……

Biochemistry of thyroid hormones biosynthesis

Chemistry of thyroid hormones

Chemistry of thyroid drugs

Pharmacophore and SAR of thyroid drugs

Appling medicinal chemistry of thyroid drugs to


common clinical decision
Recall anatomy and physiology of thyroid
gland
benign
Biggest endocrine
gland

Upper portion of
trachea and below
the larynx

Consist of 2 lobe
connected by
isthmus

About 25 g weight
Recall anatomy and physiology of thyroid
gland
04749891ensiafthyroidh
mmmm 1 0 51829
Follicle is a sphere, cyst-like
bringing 300mA
pabffffrae structure approximately 300
Ir
1 Apical m diameter and is filled
with gelatineous colloid
9 9 68800 02,40gelatin
Main component of colloids
TG
is glycoprotein called
glytoprotein
thyroglobulin (Tg)
rn
grnthyroglobuli
tag.morontoalcitonin
Recall anatomy and physiology of thyroid
gland

UB's
The follicle cells seem to fulfill the function of secretory and
mum
9008
absorptive cells 6090928418

In addition, the follicle cells has the specific ability to


metabolize iodine, comprising the accumulation of iodine,
onionu
iodination of tyrosyl residue in Tg, and coupling of the
iodinated tyrosyl to form thyroid hormones marinethyroid

Paracellular cells, called light cells or C cells, produce


thyrocalcitonin
8 naitthyrocalcitonin
Hormones of thyroid gland

Thyroid hormones are iodinated amino acids derived from


mmm
L-tyrosine which are synthesized in the thyroid gland and
run
stored as amino acid residues of Tg metabolise Vos
n y i 5 F
aminoa r
r i Tq
2 I
5 3
thyrosiine Isoia
LL
245082177600

vimeo.mn
intermediate
rain thyroid
Bringin I 382
damnit iodine 408M
MIT = monoiodo-L-tyrosine DIT = diiodo-L-tyrosine
T3 = 3,5,3 -triiodo-L-thyronine T4 = 3,5,3 ,5 -tetraiodo-L-thyronine
rT3 (Reverse T3) = 3,3 ,5 -triiodo-L-thyronine
Tg
Hormones of thyroid gland
t II
Glehoh8ET3gT4tb5UIodine4Uo7sn70fTfjjg6uMuInfeI5DITtO.s'T
Thyroglobulin (Tg) serves as the matrix for the synthesis of T 4
and T3 and as the storage form of the hormones and iodide
Biopolymers glycopeptides ohhonotamingo
my
Tg is a large glycoprotein with MW 660,000 Da which
account for about one-third of the weight of thyroid gland138098
Althgroi
6 10 fog MIT gland
Tg carries an average of 6 tyrosyl residues as MIT, 5 residues
5126 17 0.3 win Tg
14
as DIT, 0.3 residues as T3 and 1 residues as T4
vimeo.jo innit Ty 266458308 1
Normal thyroid gland contains enough potential T 4 to Inna
maintain a euthyroid state for 2 month without new synthesis
I

JPY02 I
8120
I

10808819 1
On 0
I
O

Os coupling

1 Dina

2 MIT DIT
I

Biosynthesis of thyroid gland

Active uptake of iodide by follicular cells


around I
Dietary iodide, iodide leaked from the thyroid gland, and
F
ace
mmmm 12
reclaimed hormonal iodide provide iodide input hooontdynhism
6Pametabolise I
I
inner
Thyroid gland iodide uptake, renal elimination, and small imbibe
mum
biliary excretion provide iodide loss
07107678

anmetabo
n'unOoog

thyroidgl
Biosynthesis of thyroid gland

I 296906072765U
Active uptake of iodide by follicular cellsload
ohcond
The mechanism to iodide uptake is iodide pump which
regulated by TSH
mum
pituitary
Iodide pump maintain the ratio of thyroid iodide to serum
A2UnoYb6nTC0nc.oios9fwofggnwvnc.thyroidgland
iodide (T:S ratio) of about 20:1. If more than 100:1
R2UBWM8oT9I
hyperactive gland fgnai1serum206ri7

- -
This process may be blocked inorganic ions (SCN and ClO4 )
e
pump 070 In block
of 8 PM unaval II
q noo
g
Biosynthesis of thyroid gland

4202
I Or
Oxidation of iodide and formation iodotyrosines
I b giguotag
Iodide must be oxidized by H2O2 and thyroperoxidase (TPO)
-
to serve as an iodinating agent (OI ) higher oxidationstate
stabndotyrosineta
TPO is also essential for the incorporation of iodide into
tyrosine residues in Tg and coupling of iodotyrosyl residues

O from DIT to form T4 and T3


WITH gW1anNADPHql9viIondd08lt202
I µ.gg 00h27
Ooisomsboin
marabinstiltTPO naugala OIodide I jog'ircell
Biosynthesis of thyroid gland

Coupling of iodotyrosine residues

Be catalyzed by TPO at Tg and involves the coupling of two


outer rings from DIT to become T4 and the coupling of two
outer rings from MIT with DIT to become T3

The location of iodotyrosyl residues with Tg creates an


optimal spatial alignment, facilitating the coupling reaction

This process can be blocked by thiourea, thiouracils, and


sulfonamides
Biosynthesis of thyroid gland

Proteolysis of Tg and release of iodothyronines

The release of thyroid hormone begins with the resorptioon of


Tg via endocytosis into cells and followed by proteolysis by
lysosomal digestive enzymes

Proteolysis yields MIT, DIT, T3, and T4

MIT, DIT and idodide are recycled for thyroid gland

T3, and T4 are secreted into circulation


Biosynthesis of thyroid gland

Conversion of Thyroxine to triiodothyronine

T4 is usually considered to be a prohormone

T4 has longer t1/2 and much higher than T3

The conversion is as obligate step in the physiological action


of thyroid hormone

In the peripheral tissues, approximately 33% of T 4 undergoes


5 -deiodination to give T3 and 40% undergoes deiodination of
the inner ring to yield rT3
Biosynthesis of thyroid gland

Conversion of Thyroxine to triiodothyronine

5 -deiodination of T4 is a reductive process catalyzed by


iodothyronine 5 -deiodinases, referred to 5 -deiodinases
(5 -D)

Approximately 80% of T3 is derived from circulating T4


Biosynthesis of thyroid gland

Transport of thyroid hormones

>99% of circulating thyroid hormone is bound to plasma


proteins but can be liberated rapidly for entry into cells

Thyroid hormone-binding proteins are comprised of thyroid-


binding globulin (TBG), transthyretin (TTR or thyroxine-
binding prealbumin), human serum albumin (HSA), and
lipoprotein

Abnormal concentrations of binding proteins result in


maintaining normal free thyroid hormone concentration
Biosynthesis of thyroid gland

Transport of thyroid hormones

Their functions are most probably to ensure a constant


supply of thyroid hormones to the cells and tissues by
preventing urinary loss, protect the organism against
abrupt changes in thyroid hormone product and
degradation, protect against iodine deficiency, and target
the amount of thyroid hormone delivery by ensuring a
site-specific, enzymatic alteration of TBG
Biosynthesis of thyroid gland

Metabolism and excretion

Deiodination to T3 (outer ring) and/or rT3 (inner ring) via 5 -D

Conjugation of phenolic OH of outer ring with sulfonate or


glucuronic acid (at liver) and is excreted by renal

After hydrolysis in intestine by bacterial -glucuronidase,


iodothyronine glucuronides are rapidly excreted in bile
enterohepatic recycling

Thyroid hormones can also undergo deamination and


decarboxylation
Biosynthesis of thyroid gland

Metabolism and excretion


Biosynthesis of thyroid gland

Physiologic action of thyroid hormones

Oxygen consumption and calorigenesis

Respiratory exchange in hypothyroid and in hyperthyroid

Also basal metabolic rate (BMR) and temperature

Promote glucose absorption, hepatic and renal gluconegenesis,


hepatic glycogenolysis, and glucose utilization in muscle and adipose

Differentiation and protein synthesis

Deficiency of thyroid hormone during the critical period when


developing human brain cretinism
Biosynthesis of thyroid gland

Control of thyroid hormone biosynthesis

Primary regulator is the pituitary hormone TSH (glycoprotein,


MW 28,000 Da)

TRH (Thyroid-releasing hormone) is controller of TSH

TRH is three amino acid (pyro-glutamyl-histidine-proline


amide)
Biosynthesis of thyroid gland

Diseases involving the thyroid gland

Hypothyroid Hyperthyroidism

Goiter Hashimoto disease

Cretinism Generalized resistance


to Thyroid hormones
Myxedema
Thyroid cancer
Therapeutic agents

Thyroid replacement therapy

Natural thyroid hormone preparation

Desiccated thyroid and Tg are derived from thyroid glands of


domesticated animal

T4, T3, DIT, and MIT are released from the proteolytic activity of GI
enzymes

Potency is based on total iodine content or bioassay

Desiccated thyroid preparation (Thyroid USP) are powder of bovine or


porcine thyroid glands compressed into oral tablet
Therapeutic agents

Thyroid replacement therapy

Natural thyroid hormone preparation

A diluent is usually present, because the preparations (especially of


porcine) exceed the 0.17% - 0.23% iodine content

Most comments regarding desiccated thyroid also apply to partially


purified Tg, because the two preparations differ in their total and
relative amounts of T4 and T3
Therapeutic agents

Thyroid replacement therapy

Synthetic thyroid hormone preparation

Levothyroxine sodium (T4)

o Has slower onset of action than T3 and desiccated thyroid preparation

o Strength : 25 – 300 g

Liothyronine sodium (T3)

o Choice when need rapid onset or cessation of activity


Therapeutic agents

Thyroid replacement therapy

Synthetic thyroid hormone preparation

Liotrix (Thyrolar)

o Mixture of T4 and T3 (4:1)

Dextrothyroxine (dT4, Choloxin)

o (+)-stereoisomer of T4

o Introduce in hypocholesterolemic-hypolipidemic therapy with the premise


that it would be void of calorigenic effect
Therapeutic agents

Thyroid imaging agents

Radioiodine
131 125
Only isotopes I and I have been used consistently

For diagnosis use and/or treatment


131 131
I decays to Xe with emission of 0.6-meV -particle and 0.3-meV
-rays and has a half-life of 8 days
125 125
I decays to Te with emission of 27-keV x-rays and 35.5-keV -
rays and has a half-life of 60 days
Therapeutic agents

Thyroid imaging agents

Radioiodine
131
Absorption of I -radiation highly localized desctruction of thyroid
follicles advantage: avoid surgical risks
- -
Perchlorate (ClO4 ) and pertecnetate (99mTcO4 )

Perchlorate competitively inhibit the uptake of iodide but


curtailed after aplastic anemia and severe renal damage

Pertecnetate is used for study and imaging of thyroid gland


Therapeutic agents

Antithyroid drugs for hyperthyroidisms

Iodide

Iodide decreases the vascularity of thyroid gland and lowers the


elevated BMR

Excess iodide might change the conformation of Tg, making the


protein less susceptible to thyroid proteolysis

Iodide (Lugol’s solution; Strong Iodine solution USP) as KI is


administered 2 wk

Side effect; allergic reaction and common cold-like symptom


Therapeutic agents

Antithyroid drugs for hyperthyroidisms

MMI, PTU, and related compounds

Thioamide class potent inhibitor of TPO,


no effect on iodide pump

Most clinical uses are thioureylenes, which


are five- or six-membered heterocyclic
derivatives of thiourea, thiouracil (PTU), and
thioimidazole 1-methyl-2-mercaptoimidazole
(MMI, Tapazole)
Therapeutic agents

Antithyroid drugs for hyperthyroidisms

MMI, PTU, and related compounds

Uptake of these drugs is stimulated by TSH and inhibited by iodide

Low-dose MMI is safer than PTU where toxicity of MMI is common in


>40 year old but PTU in younger

6-Alkylthiouracil showed maximal antithyroid activity

C2 thioketo/thioenol and unsubtituted N1 is essential for activity

Enolic OH at C4 in PTU and the presence of alkyl at C3 and C6


enhance activity
Therapeutic agents

Thyrotoxicosis

Hyperthyroidism is a cause of thyrotoxicosis

Because symptoms of thyrotoxicosis resemble those of


adrenegic overstimulation, attempts to decrease such
symptoms by adrenergic blockade have been undertaken

Reserpine and guanethidine, both of which are depleters of


catecholamines, and propanolol, a -blocking agent, have
been used efficiently to decrease the tachycardia, tremor,
and anxiety of thyrotoxicosis
Therapeutic agents

Goitrogens and drug affecting thyroid function

Goitrogenic effect hypothyroidism

Lithium inihibit hormone secretion use as adjunct


in initial treatment of thyrotoxicosis

Goitrin TPO inhibitor


SAR of thyroid analogs

Aliphatic side chain

L-isomer is more active than D-isomer


-
COOH and number of atoms connecting it to ring are more
important than intact zwitterionic alanine side chain
- -
Formic, propionic and butyric COOH < acetic COOH
-
Ethylamine < COOH
SAR of thyroid analogs

Alanine-bearing ring (inner ring or -ring)

Remove both I loss of perpendicular orientation of


diphenylether loss activity

Br instead I retain activity

I is not essential for activity

Larger alkyl at C3 and C5 decrease activity


SAR of thyroid analogs

Bridging atom

Replacement by S or methylene activity

Phenolic ring (Outer ring or -ring)

Unsubstituted loss activity

Replace 3 by OH or NO2 loss activity

At 3 , F<Cl<Br<I and CH3<CH2CH3<CH(CH3)3


SAR of thyroid analogs

Phenolic OH

Weakly ionized OH at 4 is essential and optimum

Replace 4 by NH2 loss activity

pKa of T4 is 6.7 and of T3 is 8.5 greater acidic, strong


affinity to plasma protein and higher t1/2
SAR of thyroid analogs

Conformational properties of thyroid analogs


SAR of thyroid analogs

Conformational properties of thyroid analogs

Perpendicular to the planes of inner ring would be favored


to minimize interaction b/w bulky 3,5-I and 2 ,6 -H

This orientation, 3 and 5 are not equivalent and 3 -I will go


to distal
Calcium Homeostasis
Learning Objectives

After this class, the students have to understand……

Hormonal regulation of serum calcium level

Normal physiology and disease related calcium


homeostasis

Pharmacophore and SAR of drugs for disease related


calcium homeostasis

Appling medicinal chemistry of drugs disease related


calcium homeostasis to common clinical decision
Hormonal regulation of serum calcium level
Hormonal regulation of serum calcium level

Calcitonin

32-amino acid peptide synthesized in parafollicular “C” cell

Disulfide bridge (1 7) is critical


Hormonal regulation of serum calcium level

Parathyroid hormone

115-amino acid peptide preprohormone synthesized in


RER of parathyroid gland
Hormonal regulation of serum calcium level

Vitamin D

Derived from cholesterol, vitamin D is bisynthesized from


its prohormone cholecalciferol (D3)

Two steps oxidation


1st oxidation to 25-hydroxycholecalciferol [25(OH) D3: calcifediol:
Calderol] by vitamin D 25-hydroxylase

2nd oxidation to 1,25-dihydroxycholecalciferol [25(OH)2 D3: 1,25-


calcitriol: Rocaltrol: Calcijex] by vitamin D 1 -hydroxylase
Hormonal regulation of serum calcium level

Vitamin D
Disease states associated with abnormal
calcium homeostasis

Osteoporosis Pseudohypoparathyroidism
Osteopetrosis Hyperparathyroidism
Hypocalcemia Rickets and osteomalacia
Hypercalcemia Paget disease of the bone
Hypoparathyroidism
Drug therapies used to treat osteoporosis

Antiresorptive agent

Estrogen analogs – Estrogen replacement therapy


MOA: not yet elucidated, but possibly associatedwith inhibition of
osteoclast activity improve calcium absorption, promote
calcitonin biosynthesis, and vit. D receptor on osteoclast

Examples: 17 -estradiol, estrone sodium sulfate, or 17-ethinyl


estradiol
Hormonal regulation of serum calcium level

Antiresorptive agent

Selective estrogen receptor modulators (SERM)


Examples: raloxifene (Evista), lasofoxifene (Fablyn), ospemifene,
bazedoxifene, and toremifene

Raloxifene is the first SERM approved for the prevention of


osteoporosis in postmanupausal woman

Raloxifene, a benzothiophene derivatives, may be consideres as a


semirigid analog of tamoxifen
Drug therapies used to treat osteoporosis

Antiresorptive agent
Hormonal regulation of serum calcium level

Antiresorptive agent

SAR of SERM
Only pure antiestrogen are 7 -substituted estrogen

A ring phenol is critical for interaction with the portion of estrogen


receptor (ER) protein or referred as the activation factor-2 (AF-2) –
mimic to 3-OH of estrogen

The orientation of three aryl in a propeller type of arrangement is


important for tight receptor binding and biological activity

In raloxifene, substituted benzothiophene ring mimic to estrogen


ring A
Drug therapies used to treat osteoporosis

Antiresorptive agent

Bisphosphonates
Design to mimic pyrophosphate, where O in P-O-P is replaced by C to
create nonhydrolyzable backbone

MOA: Selectively bind to the hydroxyapatite portion of the bone and


can bind to and stabilize calcium phosphate efficiently inhibits
osteoclast proliferation, osteoclast activity, and reduce osteoclast life
span

Examples: etidronate disodium (Didronel) and tiludronate disodium


(Skelid), Alendronate sodium (Fosamax), Risedronate sodium
(Actonel), Iabndronate sodium (Boniva), and Zoledronic acid (Reclast)
Drug therapies used to treat osteoporosis

Antiresorptive agent

Bisphosphonates
Drug therapies used to treat osteoporosis

Antiresorptive agent

SAR of bisphosphonates
Substitution at central C of geminal phosphonate affect
physicochemical and biological properties

R1 as OH maximize the affinity

R2 as NH2 improve potency

R2 as n-propyl-NH2 is more potent than ethyl or hexyl

Alkylation of NH2 improve potency

Linkage b/w central C and basic heterocyclic side chain of of 3rd


generation : NH>CH2>S>O
Drug therapies used to treat osteoporosis

Antiresorptive agent

Calcitonin (Calcimar [IV, SC]; Miacalcin and Fortical [nasal


spray])
Approved for postmenupausal osteopososis, hypercalcemia of
malignancy, and Paget disease of the bones

Source: salmon (preferred), eel, human, and procine

32 amino acid

Salmon calcitonin is 50-fold more potent than of human with longer


duration
Drug therapies used to treat osteoporosis

Antiresorptive agent

Calcitonin (Calcimar [IV, SC]; Miacalcin and Fortical [nasal


spray])
Drug therapies used to treat osteoporosis

Bone-forming agents

Teriparatide
Since 2002, FDA approved for postmenupausal osteopososis,
glucocorticoid-induced osteopososis, and primary or hypogonadal
osteopososis

Recombinant human PTH 1-34 increase osteoblast

32 amino acid

Avoid in patients with risk for osteosarcoma


Drug therapies used to treat osteoporosis

Bone-forming agents

Inorganic salt
Calcium salts – 1,300 mg/day of elemental calcium for teenagers,
1,000 mg/d for premenupausal women and men, and 1,200 mg/d for
postmenupausal women
▪ Absorption of Ca at GI 25-40%

▪ More soluble salt (citrate, lactate, and gluconate) more absorb

Sodium fluoride (NaF)


▪ Promote proliferation and activity of osteoblast
Drug therapies used to treat osteoporosis

Monoclonal antibody-based therapies

RANKL inhibitor - Denosumab (Prolia)

Cathepsin K inhibitor – Odanacatib

Miscellaneous
Strontium ranelate (Protelos)
Drug therapies used to treat
hyperparathyroidism

Cinacalcet HCl (Sensipar)

Type II calcimimetic agent

Improve CaSR sensitivity to calcium


Drug therapies used to treat hypercalcemia
of malignancy

Zoledronate (Zometa)

Pamidronate disodium (Aredia)

Gallium nitrate (Ganite)


Drug therapies used to treat
hypoparathyroidism
Parathyroid hormone [rDNA 1-84]

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