Advanced Medicinal Chemistry

Filippo Minutolo

CFU 3 (21 hours)

Educational objectives

To provide the knowledge of:

1) the “chemistry” involved in the action of drugs and prodrugs thereof;

2) the structural considerations in the molecular design.

Recommended basic knowledge

General Chemistry, Organic Chemistry, Medicinal Chemistry

Program

• “Drug-likeness”, ADMET, interactions

• Prodrugs: structural design, types of activation (enzymatic/nonenzymatic)

• Soft drugs

• “Intelligent” prodrugs: hypoxia-selective chemotherapeutics;

selective activations (ADEPT, ADAPT, MDEPT, etc.)

• Molecular complexity, pharmacoforic elements and synthetic accessibility

Advanced Medicinal Chemistry

Filippo Minutolo

CFU 3 (21 hours)

• Correlations between chemical features and biological properties

• The “chemistry” behind the action of a drug

Reference textbooks and articles

R. B. Silverman “Organic Chemistry of Drug Design and Drug Action”, 2nd Edition,

Elsevier - Academic Press, San Diego, CA - USA, 2004. [ISBN 0-12-643732-7]

C. G. Wermuth “The Practice of Medicinal Chemistry”, 3rd Edition,

Elsevier – Academic Press, London, UK, 2008. [ISBN 0-12-744481-5]

Scientific articles from the recent literature, which will be provided during classes.

T. L. Lemke, D. A. Williams “Foye’s Principles of Medicinal Chemistry” (7th Ed.),

Lippincott Williams & Wilkins, 2013. [ISBN 978-1-60913-345-0]

E. H. Kerns, L. Di. “Drug-like Properties: Concepts, Structure Design and Methods”,

Elsevier - Academic Press, San Diego, CA - USA, 2008. [ISBN 978-0-1236-9520-8]

G. L. Patrick “An Introduction to Medicinal Chemistry” (5th Ed.), Oxford University

Pressi, 2013. [ISBN 978-0-19-969739-7]

Advanced Medicinal Chemistry

Filippo Minutolo

CFU 3 (21 hours)

Vancomycin

Glycopeptidic antibiotic

Chem. Rev. 2005, 105, 425-448.

aglicone still active

inhibition of peptidoglycan biosynthesis

alteration of bacterial membrane permeability

mechanism of action and resistance

complexation with tripeptide

(N-Ac-L-Lys-D-Ala-D-Ala)

peptidoglycan precursor

Chem. Rev. 2005, 105, 425-448.

mutation

(N-Ac-L-Lys-D-Ala-D-Lac)

resistance

Vancomycin

sensible bacteria

resistant bacteria

Chem. Rev. 2005, 105, 425-448.

HN

O

HN

O

O

repulsione

O

O

convivenza

vancomicina

D-Ala-D-Lac D-Ala-D-Lac

vancomicina de-ossigenata

sensible bacteria

resistant bacteria

mechanism of action and resistance

Vancomycin

mutation

(N-Ac-L-Lys-D-Ala-D-Lac)

resistance

vancomycin de-oxygenated vancomycin

repulsion tolerance

structural modification (O-off!) against resistant bacteria

J. Am. Chem. Soc. 2006, 128, 2885-2892.

OH

OO

NH

HN

H

O

N

H2N

O

O

NH

OH

Cl

O

NHMeHN

ClO

N

O H H

H

HOOCH

HO

HO OH

OH

O

O

O

O

NH

O

N

HN

H

H

L-Lys-D-Ala-D-Lac

vancomicina de-ossigenata

active on non-mutated form too

HN

O

HN

O

O

repulsione

O

O

convivenza

vancomicina

D-Ala-D-Lac D-Ala-D-Lac

vancomicina de-ossigenata

Vancomycin

vancomycin de-oxygenated vancomycin

repulsion tolerance

de-oxygenated vancomycin

mutation

(N-Ac-L-Lys-D-Ala-D-Lac)

resistance

Use of boron atoms in Medicinal Chemistry

Boron compounds

• estrogenic ligands

• antitumor agents

• antifungal agents

• antiviral agents

• antimalaric agents

• BNCT

Similarities between C=C and B-N

Chemistry & Biology 2007, 14, 659-669.

Estrogenic ligands

Antitumor drugs in clinical use

Nature Chem. Biol. 2006, 2, 689-700.

CML = chronic myelogenous leukemia

GIST = gastro-intestinal stromal tumor

N

N

N

O

H

NH

O BOHHO

BORTEZOMIB

Boronic acids in Medicinal Chemistry

Antitumor agents

• inhibitors of tubulin polymerization

Boronic acids in Medicinal Chemistry

Antitumor agents

• proteasome inhibitors

N

N

N

O

H

NH

O BOHHO

BORTEZOMIB

Boronic acids in Medicinal Chemistry

Antitumor agents

• histone deacetylase (HDAC) inhibitors

Boronic acids in Medicinal Chemistry

Antitumor agents

• steroid-sulfatase (STS) inhibitors

26: competitive inhibitor (Ki = 2.8 M)

27a,b: non-competitive inhibitors (Ki = 250 nM, both)

Boronic acids in Medicinal Chemistry

Antitumor agents

• EGFR tyrosine kinase inhibitors

Erlotinib

(Tarceva)

Boronic acids in Medicinal Chemistry

Antitumor agents

• Hypoxia-Inducible-Factor 1 alpha (HIF-1 ) inhibitors

Boronic acids in Medicinal Chemistry

Boron-containing antifungal agents

Science 2007, 316, 1759-1761.

J. Med. Chem. 2006, 49, 4447-4450.

Onychomycosis: caused by some types of dermatophytes, inparticular by

Trichophyton rubrum and Trichophyton mentagrophytes

MIC varying from 0.25 M to 1 M

inactive analogues

6-member ring emiacetal lactone

Science 2007, 316, 1759-1761.

J. Med. Chem. 2006, 49, 4447-4450.

target: one of the amminoacil – transfer-RNA synthetase (AARS), LeuRS.

mechanism of action:

formation of a cyclic boronic ester with cis-1,2-diol of AMP present in the editing site of

LeuRS (X-ray)

Boron-containing antifungal agents

LeuRS

editing site

LeuRS

editing site

antimalarial agents

Bioorg. Med. Chem. Lett. 2011, 21, 644-651.

J. Med. Chem. 2011, 54, 1276-1287.

Design, Synthesis, and Structure-Activity

Relationship of Trypanosoma brucei

Leucyl-tRNA Synthetase Inhibitors as

Antitrypanosomal Agents

antitrypanosomal agents

Boron-containing antibacterial agents

insensible to -lactamases

J. Med. Chem. 2009, 52, 6097-6106.

bacterial transpeptidase: mechanism

carboxy

peptidase

cross-linked

peptide

J. Med. Chem. 2009, 52, 6097-6106.

bacterial transpeptidase inhibitors: -lactams vs. boronic acids

-lactams

boronic acids

Boron-containing antibacterial agents

insensible to -lactamases

J. Med. Chem. 2009, 52, 6097-6106.

Boron-containing antibacterial agents

insensible to -lactamases

cavity in the

enzyme

active-site

Med. Chem. Comm. 2011, 2, 390-395.

Study of the mechanism of inibition (11B-NMR)

model enzyme: a serine-protease ( -chymotrypsin, CT)

Compound in pre-clinical development (dermatological infections)

Boron-containing antibacterial agents

insensible to -lactamases

Anti-hepatitis C agents: inhibitors of HCV-NS3 protease

Bioorg. Med. Chem. Lett. 2009, 19, 180-183.

Ki = 14 nM Ki = 0.2 nM

-ketoamide boronic acid

boronic inhibitor

Anti-hepatitis C agents: inhibitors of HCV-NS3 protease

Bioorg. Med. Chem. Lett. 2009, 19, 180-183.

Ki = 14 nM Ki = 0.2 nM

-ketoamide boronic acid

boronic inhibitor

Boron Neutron Capture Therapy (BNCT)

http://web.mit.edu/

-Particles destroy hypoxic cells too (≠ -rays, which need O2)

Minimum efficient concentration: 20 g di 10B per gram of tumor (0.002%)

active isotope (10B): 20% (11B, 80%, inactive)

4-Borono-L-phenylalanine

Radiother. Oncol. 1993, 27, 46-54.

carboranes

very stable structures (aromaticity, Huckel rule)

high density of boron atoms (however, 10B: 20%)

B B

BB

B

B

B

B

B

B

B B

B

C

B

B

B

B

B

B

B

CH

H

H

H

R'

RR'R

o-carborano

synthesis

o-carborane

carboranes

very stable structures (aromaticity, Huckel rule)

high density of boron atoms (however, 10B: 20%)

“enriched” carboranes

J. Am. Chem. Soc. 2007, 129, 6507-6512

catalytic enrichment reaction with [10B]-diborane

enrichment

conjugated carboranes

Coord. Chem. Rev. 2002, 232, 173-230.

high uptake of sugars (especially Glu) in tumors

carboranes conjugated with glucose (18), lactose (16) e maltose (17)

carboranic analog of aspirin

lipophilicity

cell membrane permeability

ChemMedChem 2009, 7, 746-748.

Complexity, pharmacoforic elements, synthesis

Acc. Chem. Res. 2008, 41, 40-49.

FOS = function oriented synthesis

FOS = function

oriented

synthesis

natural

antimalarial

agent

FOS = function

oriented

synthesis

activation by means of a Bergman cyclization (irradiation or pH):

DNA break

Acc. Chem. Res. 2008, 41, 40-49.

Complexity, pharmacoforic elements, synthesis

FOS = function

oriented

synthesis

microtubule destabilization:

anti-neoplastic activity.

Acc. Chem. Res. 2008, 41, 40-49.

Complexity, pharmacoforic elements, synthesis

FOS = function

oriented

synthesis

antilipemic

Acc. Chem. Res. 2008, 41, 40-49.

Complexity, pharmacoforic elements, synthesis

FOS = function

oriented

synthesis

antibacterial

J.Med. Chem. 2010, 53, 3793–3813

Complexity, pharmacoforic elements, synthesis

Drug likeness

Launch,

Marketing

etc.

Manufac-

turing

Clinical

Phase III

Clinical

Phase II

FTIH

To

PoC

Candidate

to Clinical

Candidate

Lead to

Candidate

Hit to

Lead

Screen

to Hit

Target to

Validated

Target

Gene to

Function

Hit: dose-dependent good activity in

preliminary screening

Candidate: efficacy and safety in vivo,

large-scale economic synthesis

Lead: satisfactory potency and selectivity;

suitable physico-chemical and

pharmacokinetic properties; lack of toxicity

Drug development process

Drug likeness

• higher chances of success

• reduced times of the development phase

• reduced costs of the development phase

1) privileged structures

2) ADME-Tox

Drug likeness

1) privileged structures

C. G. Wermuth “The Practice of Medicinal Chemistry”, 2nd Edition,

Elsevier – Academic Press, London, UK, 2003. [ISBN 0-12-744481-5]

Pag.151, Fig.10.3.

A

A

diphenylmethane

N

spiropiperidine

N

NN

N

biphenyltetrazole

N

N

O

benzodiazepine

NO

benzazepine

O

2,2-dimethylbenzopyran.

J. Med. Chem. 1996, 39, 2887-2893.

1) privileged structures

ChemMedChem 2007, 2, 861-873.

1 bis) non-desired structures

sub-structures present in drugs causing arrhythmia

Nature 2007, 448, 645-646.

1 tris) “consolidated” structured

9990 drugs available

J. Med. Chem. 2008, 51, 1214-1222.

1) “kinase likeness” – privileged structures for kinase inhibitors

J. Med. Chem. 2008, 51, 1214-1222.

1) “kinase likeness” – privileged structures for kinase inhibitors

J. Med. Chem. 2008, 51, 1214-1222.

1) “kinase likeness” – privileged structures for kinase inhibitors

J. Med. Chem. 2008, 51, 1214-1222.

“2-0 rule” + bisarylaniline structure

1) “kinase likeness” – privileged structures for kinase inhibitors

J. Med. Chem. 2010, 53, 1413-1437.

Kinase ATP-site

1) “kinase likeness” – privileged structures for kinase inhibitors

Drug likeness

ADMET considerations

A = absorption

D = distribution

M = metabolism

E = excretion

Tox = toxicity

in the early stages of drug-discovery

ADMET

ChemMedChem 2006, 1, 920-937.

Drug likeness

ADMET considerations

A = absorption

D = distribution

M = metabolism

E = excretion

Tox = toxicity

in the early stages of drug-discovery

Toxicity predictions

Drug. Discovery Today 1997, 2, 382-384.

Chemically reactive groups:

NO!

Drug likeness

toxicity Case of rofecoxib (COX-2 inhibitor)

Tetrahedron Lett. 2005, 46, 927-929.

OO

H

H

SO2CH3

N

N

SO2NH2

CF3

H3C

NO

SO2NH2

CH3

1, rofecoxib 2, celecoxib 3, valdecoxib

OO

H

H

ArPh

OHO

ArPh

H OO

ArPh

H ODO

ArPh

H OO

D

H

ArPh

OO

D

D

ArPh-H

+D2O

A B C D E F

4

OO H

SO2CH3

O2

(aria)

OO

SO2CH3

OH OO

SO2CH3

O

+

5 6

H2O

Ar

COOHHOOC

Ph

Nu- Ar

COOH

Ph

Nu

O

7

8