166

33Amides

Amides are a ubiquitous functional group in living organisms (peptides, proteins).Most unnatural amides are sufficiently stable to serve as oral drugs, and only rarelyquick enzymatic hydrolysis occurs (Table 33.1). Amides that are chemically reactivetoward nucleophiles, such as those derived from highly electrophilic carboxylic acids(e.g., trifluoroacetamides), will also undergo fast metabolic hydrolysis in vivo. Ifan amide resembles the final or first amide bond in a peptide with a positive ornegative charge close to the amide bond, quick hydrolysis by an aminopeptidaseor carboxypeptidase may occur (Scheme 33.1). Similarly, endopeptidases maycleave uncharged peptidomimetics. Peptidases are, however, highly selective, andmost unnatural amides will not be substrates of these enzymes. As in esters andcarbamates, steric shielding will also inhibit the enzymatic hydrolysis of amides.

H3N

HN

NH

HN

NH

HN

NH

O

O

O

O

O

O

O

O

AminopeptidasesExopeptidases

Carboxypeptidases

R

R

R

R

R

R

R

Endopeptidases

Scheme 33.1 Metabolism of peptides.

The absorption of highly insoluble amines or alcohols from the gastrointestinaltract can be enhanced by acylation with glycine. Aminopeptidases present in theepithelium of the intestine will rapidly deacylate the prodrug and regenerate theactive compound, as exemplified by the benzodiazepine prodrug rilmazafone andthe antihypotensive midodrine (Scheme 33.2).

Lead Optimization for Medicinal Chemists: Pharmacokinetic Properties of Functional Groups and OrganicCompounds, First Edition. Florencio Zaragoza Dorwald. 2012 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2012 by Wiley-VCH Verlag GmbH & Co. KGaA.

33 Amides 167

N

N

Cl

Cl

NN

O N

O

N

ClCl

N

N O

N

H2N

O

N

ClCl

N

N O

N

NH

H2NO

Rilmazafone

Amino-peptidase

OHHN

ONH2

OMe

MeO

Midodrinet1/2 25 min

Amino-peptidase

OHNH2

OMe

MeO

Desglymidodrinet1/2 3–4 h

F 93% (drug on oraldosing of midodrine)

Scheme 33.2 Amides as prodrugs.

Acylation with glycine, alanine, or short peptides can be used to enhance solubilityof a compound for a liquid, parenteral formulation (Scheme 33.3). A parenteralformulation may be useful even if the drug is orally bioavailable, for instance,if the drug is hepatotoxic or must be given to unconscious patients. Parenteraldosing also evades first-pass metabolism and CYP (cytochrome P450) induction orinhibition. Amide-based prodrugs can also be used as slow-release formulations ofshort-lived drugs.

N N

OCO2H

N

F

F

F

H2N

H

H

N N

OCO2H

N

F

F

F

NH

H

H

OHN

OH2N

Alatrofloxacin(for parenteral administration)

in vivo

few minutes

Trovafloxacint1/2 11 h, F 90%

NS

O O NO

Ph

CO2H

H

in vivo NHS

O OHO

Captoprilt1/2 2.2 h, F 65%

Alaceprilt1/2 5 h (captopril on

oral dosing of alacepril)

Scheme 33.3 Peptides as prodrugs.

168 33 Amides

The metabolic stability of N-unsubstituted amides (RCONH2) is difficult topredict. Sterically accessible, lipophilic amides are often hydrolyzed quickly,whereas hydrophilic or sterically shielded amides will be more stable. Some ofthe amides sketched in Scheme 33.4 have low oral bioavailabilities and half-livesbecause of amide-bond hydrolysis, but some closely related amides and esters arenot extensively hydrolyzed to carboxylic acids.

NH2

O

NH2O OH

NH2

O

Nepafenact1/2 <1 h (of acid), F 6% (rat)

fast hydrolysis to acid

Salicylamidet1/2 1–2 h, F <10%

no hydrolysis to acid

NNH2

O

N

S

SO O

Metopimazinet1/2 5 h, F 22%

hydrolysis to acid

HNOEt

OPh

Normeperidinet1/2 14–21 h

hydrolysis of ester

SO

NH2

O

Modafinilt1/2 10–12 h

hydrolysis to acid

N NH

OHO

Alvimopant1/2 10–17 h, F 1–19%

hydrolysis of amide

CO2H

N

OH2N

O

Levetiracetamt1/2 6–8 h, F 100%hydrolysis to acid

NH2

O

HN

O

OH

NH2MeO

O

OMe

Aliskirent1/2 34–41 h

F 2.6%

N

NCl

N

O NH2

Clocapraminet1/2 46 h

F 16% (dog)

Scheme 33.4 N-Unsubstituted amides as drugs.

N-Alkylamides may be dealkylated via C-hydroxylation followed by hemiaminalhydrolysis, similar to the oxidative dealkylation of amines. This metabolic transfor-mation is often observed in lactams, such as benzodiazepines (Scheme 33.5), andin cyclic imides and ureides (e.g., in barbiturates).

33 Amides 169

N

N

Cl

OF3C

N

NO

Cl

Diazepamt1/2 43 h, F 100%

in vivoN

HN

O

Cl

Nordazepamt1/2 73 h, F 99%

in vivoN

HN

O

Cl

Oxazepamt1/2 8 h, F 97%

OH

Halazepamt1/2 15 h

N

N

Cl

O

Pinazepamt1/2 1–5 h, F 40–50%

N

N

Cl

O

Prazepamt1/2 1.3 h

in vivoin vivo in vivo

Scheme 33.5 N-Dealkylation of benzodiazepines.

Table 33.1 Amides. V in l kg−1; CL in ml min−1 kg−1; Mwt in g mol−1.

t1/2 2.5 h V 2.1 DEET, AUTANF 48%∗ CL – ∗from dermal absorptionpb – Mwt 191.3 Insect repellantur 10–14% PSA 20.3 A2 Metabolism: deethylation,

log P 2.42 oxidation of CH3 to CO2H

N

O

t1/2 14 d∗ V 0.08–0.44∗ LEFLUNOMIDEF 82–94%∗ CL 0.007–0.012∗ ∗teriflunomide (see below)pb 99.4%∗ Mwt 270.2 on oral dosing of

ur Negligible PSA 55.1 A2

leflunomide; antirheumatic,log P 2.29 immunomodulator;

leflunomide is a prodrug ofits active cyanoketonemetabolite teriflunomide

NH

CF3O

NO

t1/2 15–18 d V – TERIFLUNOMIDEF <40% CL – Dihydroorotatepb >99% Mwt 270.2 dehydrogenase inhibitor,ur – PSA 73.1 A2 agent for multiple

log P 1.52 sclerosis; active metaboliteof leflunomide

NH

CF3O

CN

OH

(continued overleaf )

170 33 Amides

t1/2 4–22 h∗ V – FLUTAMIDEF – CL – ∗2-hydroxyisopropylpb 94–96% Mwt 276.2 metabolite; Nonsteroidalur Negligible PSA 74.9 A2 antiandrogen, prodrug of

log P 3.52 the active 2-hydroxy-isopropyl metabolite;Metabolism: single, twofold,and threefold hydroxylationof isopropyl group,reduction of nitro to amino,hydrolysis of amide,aromatic hydroxylation

NH

NO2

CF3

O

t1/2 12–20 h V – ROFLUMILASTF 69–92% CL – PDE4 inhibitor,pb 99% Mwt 403.2 bronchodilatorur – PSA 60.5 A2 Metabolite: pyridine-N-oxide

log P 2.31

N

NH

O

O

O

F

FCl

Cl

t1/2 4 h V 1.4∗ ANDARINEF 38–91%∗ CL 3–7∗ ∗dogpb – Mwt 441.4 Selective androgen receptorur – PSA 105 A2 modulator

log P 4.01 Metabolism: amidehydrolysis (both), reductionof NO2 to NH2

O

NH

OHO

HN

O

NO2

CF3

t1/2 4 h V – OSTARINEF – CL – Selective androgen receptorpb – Mwt 389.3 modulatorur – PSA 106 A2

log P 2.93

O

NH

OHO

NC CN

CF3

t1/2 2–16 d V 1.2–1.3 BICALUTAMIDEF 100% CL 0.8 Antiandrogen, hormonalpb 96% Mwt 430.4 antineoplasticur 0% PSA 116 A2 Metabolism: aromatic

log P 4.94 hydroxylation (ortho to F),glucuronidation

O

NH

S

F CN

CF3OO OH

t1/2 7 h∗ V 0.6 TAK-442F 53%∗ CL 12 ∗monkeypb – Mwt 480.0 Factor Xa inhibitor,ur – PSA 115 A2 antithrombotic

log P 2.77

O

NSOO

Cl

OHN NH

O

33 Amides 171

t1/2 3–4 d V 40 TARANABANTF 31%∗ CL 6.5 ∗monkeypb 100% Mwt 516.0 Cannabinoidur Negligible PSA 75.0 A2 antagonist, antiobesity

log P 7.13 agent; Metabolism: benzylichydroxylation (at C3CH)

ONH

ON

F3C

Cl

CN

t1/2 8–12 h V – AFN-1252F 82% CL – Bacterial fatty acidpb 99% Mwt 375.4 biosynthesis inhibitorur – PSA 74.9 A2

log P 0.85

O

N

NNH

OO

t1/2, plasma half-life; F, oral bioavailability; pb, plasma protein binding; ur, excretion of unchangeddrug in urine; V, volume of distribution; CL, clearance; Mwt, molecular weight; PSA, polar surfacearea; PDE, phosphodiesterase.