Female and Male Reproductive Medicinal Chemistry

Estrogens (structure)

C-18 steroids; aromatic A ring with 3-phenolic group

Progestins (structure)

C-21 steroids; unsaturated 3-keto-4-ene in A ring + ketone at C-20

Androgens (structure)

C-19 steroids; ketone at C-3 and hydroxyl at C-17

Sex hormone biosynthesis

All synthesized from cholesterol via pregnenolone; stimulated by LH

Aromatase (biosynthesis)

Converts androstenedione → estrone; testosterone → 17β-estradiol

17β-Estradiol metabolism: step 1

Oxidized to estrone (less potent) via estradiol dehydrogenase

17β-Estradiol metabolism: step 2

16α-hydroxylation → estriol (weak estrogen)

17β-Estradiol metabolism: step 3

CYP3A4 at positions 2 or 4 → catechol estrogens (2-OH or 4-OH estrogens)

17β-Estradiol excretion

Glucuronide, sulfate & glutathione conjugates in urine; estriol is major urinary metabolite

Progesterone metabolism

Reduction of 3-ketone, 20-ketone & 4,5-double bond → 5β-pregnane-3α,20-diol (inactive)

Progesterone excretion

Glucuronide conjugates of 5β-pregnane-3α,20-diol in urine

Estrogen SAR: C-3

Phenol OH at C-3 → HBD with Glu353 & Arg394; required for ER binding

Estrogen SAR: spacer

Flat hydrophobic spacer; optimal distance between OH groups = 10.3–12.1 Å

Estrogen SAR: C-17

OH at C-17 must be in β orientation → HBA with His524

Estrogen SAR: bulk

Flat hydrophobic/planar-rigid system binds ER via hydrophobic interactions

17β-Estradiol oral problem

Limited oral bioavailability; degraded in GI tract & rapidly metabolized by liver

Ethinyl estradiol (EE)

17α-ethinyl group added to 17β-estradiol → blocks first-pass oxidation → orally active; used in oral contraceptives

Mestranol

3-methoxy ether of EE; orally active prodrug → demethylated in vivo to EE

Estradiol 3-acetate ester

Vaginal ring (Femring); treats menopausal vasomotor symptoms & vaginal atrophy

Estradiol cypionate & valerate

IM esters; slowly hydrolyzed in vivo → prolonged estrogenic action up to 4 weeks

Conjugated estrogens

Sulfate esters (prodrugs) from pregnant mare urine; hydrolyzed in intestine → active phenols; treats postmenopausal symptoms

Premarin

~50-65% sodium estrone sulfate + ~20-35% sodium equilin sulfate; 6 active estrogen metabolites

Menest

≥90% sodium estrone sulfate (75-85%) + sodium equilin sulfate (6-15%); synthetically derived

Estropipate

Piperazine salt of estrone sulfate (prodrug)

Diethylstilbestrol (DES)

Nonsteroidal stilbene derivative; two phenol groups spaced like 17β-estradiol; trans isomer 10x more potent than cis

Clomiphene

Nonsteroidal triphenylethylene; ER antagonist → blocks estradiol negative feedback at hypothalamus → induces ovulation; prodrug (metabolites 100x more potent)

Clomiphene isomers

Trans (enclomiphene) more potent; given as 3:2 trans:cis mixture

Clomiphene metabolism

CYP2D6 & CYP3A4 → hydroxylated metabolites (active); metabolites are 100x more potent at ER

Progesterone SAR

Pregnane nucleus, 3-keto-4-ene, and 17β-ketone all required for progestational activity

Progesterone oral problem

Completely metabolized in first pass through liver → given parenterally

17α-acyl groups (progestins)

Not prodrugs; slow metabolism of C-20 ketone → ↑ duration of action

17α-acetoxyprogesterone

Orally active pregnane progestin

17α-hydroxyprogesterone caproate

IM or SC injection; slow release

C-6 modification (progestins)

Substituents at C-6 hinder metabolism & ↑ lipid solubility → ↑ oral contraceptive action (e.g. MPA, megestrol)

Megestrol acetate

6,7-double bond + 6-substitution → ↑ progestational activity

Ethisterone

Androstane-derived oral progestin; 17α-substituent blocks C-17 metabolism → oral activity

19-norsteroids

Lacking C-19 methyl group; ↑ progestational activity (19-norprogesterone is 8x more potent than progesterone)

Norethindrone & norethynodrel

17α-ethynyl of 19-norsteroids; 1st gen oral progestins; 17α-ethynyl blocks metabolism → ↑ progestational, ↓ androgenic activity

Norethindrone acetate

Prodrug; rapidly deacetylated to norethindrone after oral administration

Ethynodiol diacetate

Prodrug; acetylation of 17β-OH → longer duration of action

Norgestrel & levonorgestrel

2nd gen; 18-methyl of norethindrone replaced with ethyl → 18β-ethyl ↓ androgenic, ↑ progestational activity; dextro isomer inactive, levo isomer active

Norgestimate & norelgestromin

3rd gen; oxime replaces 3-keto group → ↓ androgenic activity; norelgestromin metabolized back to levonorgestrel

Desogestrel & etonorgestrel

3rd gen; contain methylidene group at C-11; desogestrel is prodrug of etonorgestrel

Dienogest

4th gen; double bond at C9-C10 + 17α-propenonitrile group

Drospirenone

4th gen; two cyclopropane rings (C6,7 and C15,16) + γ-lactone at C-17; no androgenic activity; derived from spironolactone

Mifepristone (chem)

Competitive PR antagonist; 11β-(4-dimethylaminophenyl) side chain destabilizes PR agonist conformation; propynyl + hydroxyl at C-17

Ulipristal acetate (chem)

More lipophilic than mifepristone; methyl ketone + acetoxy at C-17; longer half-life; metabolized by CYP3A4 → mono-demethyl (active) + di-demethyl (inactive)

Menopause HRT classes

Estrogens, estrogen+progestin combos, progestins, SERMs

SERMs pharmacophore

3 aromatic groups on nonsteroidal linker; trans-aryl = phenol or metabolized to phenol; cis-aryl = phenoxy + ethyl chain + basic tertiary amine

Tamoxifen

SERM; prodrug; CYP2D6 → 4-OH TAM (active); CYP3A4 → NDM TAM (inactive) & endoxifen (active); metabolites bind ER 30x more than tamoxifen; treats metastatic breast cancer

Toremifene

Triphenylethylene SERM; differs from tamoxifen by Cl on ethyl chain; CYP3A4 → NDM TOR; dealkylated → ospemifene; treats metastatic breast cancer in postmenopausal women

Ospemifene

SERM metabolite of toremifene; ER agonist in vaginal epithelium; antagonist in breast & uterus; treats dyspareunia

Raloxifene

Benzothiophene SERM; reduces invasive breast cancer risk in postmenopausal women with osteoporosis

Bazedoxifene

Indole derivative of raloxifene; binds ERα similarly

Prasterone (DHEA)

Treats dyspareunia from vaginal atrophy; metabolized → testosterone → 17β-estradiol; caution in breast cancer history

Aromatase inhibitors (AIs)

↓ estrogen production by blocking aromatase → used for hormone-dependent breast cancer

Aromatase mechanism

Contains heme (Fe) prosthetic group; 3 successive hydroxylations using 3 NADPH + O₂ → androgen → estrogen; C-19 eliminated as formate

Letrozole

Nonsteroidal triazole; reversible competitive AI; 1,2,4-triazole ring binds Fe of aromatase heme; N-4 blocks O₂ binding

Anastrozole

Nonsteroidal benzyltriazole reversible AI; two dimethylacetonitrile groups at meta positions

Exemestane

Steroidal irreversible "suicide" AI; resembles androstenedione → false substrate → irreversibly inactivates aromatase; C1-C2 double bond + methylidene at C-6; absorption ↑ with high-fat meal

Androgens (male structure)

C-19 steroids; ketone at C-3 + hydroxyl at C-17

Testosterone oral problem

Extensive first-pass metabolism in GI mucosa & liver → ineffective orally

Testosterone esters (IM)

Prodrugs; slowly hydrolyzed in vivo → release free testosterone; longer duration of action (propionate, undecanoate, cypionate)

17α-methyltestosterone

17α-methyl group slows hepatic oxidative metabolism → oral bioavailability ~70%

Fluoxymesterone

9α-fluoro added to 17α-methyltestosterone analog → 20x anabolic, 10x androgenic vs 17α-methyltestosterone; causes sodium & water retention → edema

Androgen SAR: C-17β-OH

Required for receptor attachment via H-bonding

Androgen SAR: 3-ketone or 3α-OH

Enhances androgenic activity

Androgen SAR: 17α-alkyl

Small groups block C-17 metabolism → oral activity + ↑ bioavailability

Androgen SAR: A-ring mods

Double bond at C-1, oxygen at C-2, vinyl alcohol at C-2 → ↑ anabolic activity

Androgen SAR: ring changes

Ring expansion or contraction → ↓ or destroys androgenic & anabolic activity

Androgen SAR: 5β-reduction

Reduces double bond at C4-C5 with H in 5β → no androgenic/anabolic activity; 5α-derivatives are active

Methandrostenolone

C-1 double bond in A-ring of 17α-methyltestosterone → ↑ anabolic activity; low androgenic; can cause gynecomastia (estrogenic metabolites)

Oxandrolone

2-oxasteroid (lactone in A-ring); slight androgenic activity

Oxymetholone

Vinyl alcohol at C-2; anabolic steroid

19-norandrogens

No C-19 methyl group → ↓ androgenic, retains anabolic (tissue-building) properties

Nandrolone decanoate

Ester of 19-nortestosterone; IM → slow hydrolysis → prolonged anabolic action

PDE5 inhibitors (all)

Sildenafil, vardenafil, tadalafil, avanafil; all metabolized by CYP3A4

PDE5i MOA

Sexual stimulation → NO → guanylyl cyclase → ↑ cGMP → smooth muscle relaxation → ↑ blood flow → erection; PDE5i block cGMP → GMP conversion → sustain erection

Sildenafil (chem)

Pyrazolo-pyrimidinone; CYP3A4 → N-desmethylsildenafil (active metabolite); food affects absorption; t½ ~5h

Vardenafil (chem)

Imidazotriazinone; ~20x more potent than sildenafil at PDE5; food affects absorption; t½ ~5h

Tadalafil (chem)

Pyrazinopyridoindole; 3,4-methylenedioxy on phenyl ring → ↑ potency & duration; t½ 18h; duration up to 36-48h; minimal presystemic metabolism

Avanafil (chem)

Pyrimidine derivative; (S)-enantiomer 7x more potent than (R); fastest onset (15 min); extensively metabolized by CYP3A4

PDE5i SAR

Modified purine ring mimics guanine of cGMP; heterocyclic ring system differences = key driver of potency differences between drugs

α1-adrenergic antagonists (BPH)

First-line for BPH/LUTS; relax prostate smooth muscle; do NOT shrink prostate

Quinazolines (BPH)

Alfuzosin, terazosin, doxazosin; nonselective α1 antagonists; all share 4-amino-6,7-dimethoxyquinazoline ring; differ at C-2 position (piperazine vs open chain)

Tamsulosin (chem)

Catecholamine-sulfonamide; uroselective α1A antagonist; avoid in severe sulfa allergy (aryl sulfonamide present)

Silodosin (chem)

Indole carboxamide; most uroselective α1A antagonist

5α-reductase mechanism

NADPH hydride transfer to C-5 of testosterone → enol intermediate → tautomerizes → DHT + NADP⁺; H at C-5 in α-configuration

Finasteride

Selective 5AR2 inhibitor; 4-azasteroid; 1-ene + trans A-B ring junction; mimics testosterone reduction pathway; forms dihydrofinasteride-NADP adduct (t½ ~1 month); metabolized by CYP3A4

Dutasteride

Nonselective 5AR1 & 5AR2 inhibitor; 4-azasteroid; metabolized by CYP3A4; 6'-hydroxydutasteride is equipotent to parent drug

5ARIs caution

Can be absorbed through skin; pregnant women should NOT handle tablets (fetal exposure risk)

5ARIs onset

Slow; takes 6–12 months for maximum clinical effect

Finasteride + dutasteride structure

4-aza steroids with 1-ene and trans A-B ring junction; lipophilic groups at 17β improve biological activity