MEDC 603 Fall 2007 1

Biological Discovery

High VolumeScreening

CombinatorialDiversity

Rational[Structure, Design,

Informatics]

Lead Series

Biodisposition

Toxicity

Efficacy

Pharmacokinetics

INDIND

Lead Discovery Iterative PreclinicalResearch Process R&D

Principles of Drug Design

Full Toolbox Required for Success!

MEDC 603 Fall 2007 2

Principles of Drug Design

Lipinski’s Rule of Fives

1. MW < 5002. Fewer than five H-bond donating functions3. Fewer than 10 H-bond accepting functions4. Calculated logP (ClogP) between –1 and +5

H2O

n-octanolP =

[D]Lipid

[D]Water

log P

GI Tract Vasculature(after absorption)

MEDC 603 Fall 2007 3

Lipinski’s Rule of Fives …. Examples

Principles of Drug Design

O

O

CH3

COOH

MW = 180 Da# H-bond donors = 1# H-bond acceptors = 4ClogP =2.44

O

OO

CH3CH3

CH3

O

O

MW = 282 Da# H-bond donors = 0# H-bond acceptors = 5ClogP =4.15

Aspirin

Artemisinin

MEDC 603 Fall 2007 4

Lipinski’s Rule of Fives …. Examples

Principles of Drug Design

MW = 429 Da# H-bond donors = 1# H-bond acceptors = 3ClogP = 4.74

MW = 407.5 Da# H-bond donors = 3# H-bond acceptors = 7ClogP = -0.17

RU-486 CCH3

O

OH

NCH3

CH3

C

NH

COOCH2CH3

CH2OCH2CH2NH2CH3

Cl

H3COOC

Amlodipine

MEDC 603 Fall 2007 5

Pharmacophore ………an ensemble of steric and electronic features necessary to ensure the

optimal supramolecular interactions with a specific biological target to trigger (or block) a biological response

General Approaches

Principles of Drug Design

O

N

OH

H

OHCH3

H

N

OH

CH3

HN

OH

CH3

HN

OH

CH3R

morphine morphinans benzomorphans 4-phenylpiperidines

MEDC 603 Fall 2007 6

Chemical and Biochemical Isosteres

Principles of Drug Design

Grimm’s Hydride Displacement Law

C N O F Ne

CH NH OH FH

CH2 NH2 OH2

CH3 NH3

Hinsberg’s Ring Equivalents

N

NNMe2

N

NNMe2

S

Tripelennamine Methaphenilene

Benzene, thiophene and pyridine are equivalent.e.g., H1-receptor antagonists … tripelennamine and methaphenilene

MEDC 603 Fall 2007 7

Chemical and Biochemical Isosteres

Principles of Drug Design

Friedman’s Bioisosteres …. chemical and physical properties

N

N

OH

OH

N

N

OH

OH

FUracil ….. Fluorouracil (antineoplastic)

OH

COOH

OH

CONH2

Salicylic acid ….. Salicamide (analgesic)

OH

OH

CH3

OH

OH

Estradiol ….. Diethyl stilbestrol (estrogenic)

MEDC 603 Fall 2007 8

Lengthening Alkyl Chains

Principles of Drug Design

1. Increase hydrophobicity, decrease water solubility2. Increase conformational flexibility3. May be directly involved in interaction with receptor

Bio

log

ical

Act

ivit

y

Chain Length

‘Normal’ Behavior

O

N

OH

H

OHR

H

Morphine

R Activity

-CH3 Analgesic-CH2CH3 Agonist activity decreases-CH2CH2CH3 Antagonist activity increases-CH2CH2CH2CH3 Inactive (agonist + antagonist)-CH2CH2CH2CH2CH3 Antagonist activity increased-CH2CH2CH2CH2CH2CH3 Antagonist activity increased

MEDC 603 Fall 2007 9

Flexibility of Drugs and Affinity

Principles of Drug Design

GCONF

G

Conf 1

Conf 2

RGCONF

G

Conf 1

Conf 2

R

= Bound Water

= Free Water

GOBS = GComplex + GSolv + GConf = -RT ln K

MEDC 603 Fall 2007 10

Dopamine Receptor Agonist

Principles of Drug Design

OH

OH

NMe2

OH

OH

NMe2

OH

OH

N

Me

OH

OH

N

MeIV III II I = dopamine receptor agonist

II < III < IV < I

MEDC 603 Fall 2007 11

Natural Products

~25% of drugs in use today are derived from natural products 61% of the 877 NCE introduced between 1981 and 2002 can be

traced to a natural product origin (J. Nat. Prod. (2003) 66:1022) In certain therapeutic areas, the impact is even higher, e.g., anti-

cancer (74%) and anti-bacterial (78%) Yet, natural products was de-emphasized 20 years ago because of

the advent of combinatorial chemistry! Combinatorial chemistry was not only faster and cheaper, but was

much clearer with respect to intellectual property rights The alarming decline in the number of NCEs in the past years from

an average of 30 per year to about 17 a year is correlated with

decreased interest in natural products chemistry

General

MEDC 603 Fall 2007 12

Natural products evolved for self-defense!! Amazing are the natural products that apparently evolved

only for the purpose of alleviating our diseases, e.g., the

statins Traditionally natural products are plant products, e.g.,

morphine from Papaver somniferum or digitoxin from

Digitalis Plants form the bulk of natural product suppliers … current

estimate of number of plant species on earth is ¼ million These days natural products are obtained from plants, algae,

insects, bacteria, yeast, animals, ….

Natural Products

General

MEDC 603 Fall 2007 13

• Evolution against challenges

• Structural diversity

• ‘Apparently’ unlimited quantity

• Potency

Natural Products

Advantages of Natural Products

Disadvantages of Natural Products

• Synthesis

• Isolation

• Identification

MEDC 603 Fall 2007 14

Natural Products

Typically process of drug discovery from natural sources

• Pre-knowledge helpful (cultural folklore, Chinese

Materia Medica, Indian Ayurveda, ….)

• Collect source (plant, algae, animals, ….)

• Screen extracts (organic + aqueous extractions)

• HIT!!

• Chromatographic separation

• Screen individual components

• HIT or MISS??

• Structural identification

• Independent synthesis and re-bioassay

MEDC 603 Fall 2007 15

Natural Products

Selected Examples of Natural Product derived Drugs

CH3

CH3

OO

OH

H

H

HOOOHO

OH

H3C

H3C

OH H3C

OH

CH3

CH3

OO

OH

H

H

HOOOHO

OH

H3C

H3C

OH H3C

OH

OHDigitoxin

Digoxin

Digitalis purpurea (Foxglove) and Digitalis lanata … long known for their healthy heart

effects … exert a positive inotropic effect on cardiac muscles … treatment for heart

failure

MEDC 603 Fall 2007 16

Natural Products

Selected Examples of Natural Product derived Drugs

N

N

HOH

OCH3

H N

N

OCH3

H

HOH

Quinidine Quinine

Quinidine …bark of Cinchona tree …… anti-arrhythmic drug

Quinine … no cardiac activity … anti-infective … malaria

MEDC 603 Fall 2007 17

NH

N

H H

HMeOOC

OCH3

O

OOCH3

OCH3

OCH3

MeO

Reserpine

Natural Products

Selected Examples of Natural Product derived Drugs

Reserpine …… alkaloid from Rauwolfia serpentina plant … lead from the Indian

Ayurvedic system as good for heart ... used as anti-hypertensive … the plant was a

source of ~20 different alkaloids …

MEDC 603 Fall 2007 18

Natural Products

Selected Examples of Natural Product derived Drugs

…… fungal metabolites ... first fungal metabolite was compactin which inhibited HMG-

CoA reductase … compactin is isolated from Penicillium citrinum, Penicillium

brevicompactin and Penicillium cyclopium ... an anti-fungal agent too, but toxic ...

O

CH3

OOH

R

OCH3

R

CH3

OH

COO

CH3

OH

OH

OCH3

CH3

_

Mevastatin R1 = R2 = HLovastatin R1 = H; R2 = CH3

Simvastain R1 = R2 = CH3

Pravastatin

MEDC 603 Fall 2007 19

Natural Products

Selected Examples of Natural Product derived Drugs

Dicoumarol … … coumarin derivative … coumarin is widely distributed in nature … high

concentrations in tonka beans (Dipteryx odorata) and also in Melitotus albus (sweet

clover) … a hemorrhagic disorder was observed in animals that had consumed spoiled

stuff composed of sweet clover …

O O

OH

CH3

O

O O

OH

OO

OH

*

Warfarin Dicoumarol

MEDC 603 Fall 2007 20

Natural Products

Selected Examples of Natural Product derived Drugs

Heparin … trying to find a coagulant ... accidentally found an anticoagulant! …

structure took decades to come about … now we have low molecular weight heparin

and heparin pentasaccharide …

O

OH

OH

O

COO

O

O

CH2OH

NHSO3

OHO

O

CH2OSO3

NHSO3

OH

O

OH

OH

O

COOO

O

CH2OSO3

NHSO3

OH

O

OSO3

OHO

COOO

O

CH2OSO3

NHCOCH3

OH

_

_

_

_

_

_

_

_ _

_

MEDC 603 Fall 2007 21

Natural Products

Overview of Natural Products as Drugs Status in the Period 1981-2002

0

100

200

300

400

500

V B NP NPD SNP S

V = vaccinesB = biologicalsNP = natural productsNPD = natural product derivativesSNP = synthetics derived from NPS = straight synthetics

Compiled from :Newman, D. J., Cragg, G. M., and Snader, K. M. (2003) NATURAL PRODUCTS AS SOURCES OF NEW DRUGS OVER THE PERIOD 1981 – 2002. Journal of Natural Products 66, 1022-1037.

MEDC 603 Fall 2007 22

Natural Products

Structural Comparison between Natural Products and Combinatorial Compounds

Combinatorial Compounds

Natural Products

Drugs

Data from Feher and Schmidt, J. Chem. Inf. Comput. Sci (2003) 43, 218.

Statistically defined chemical space is similar for natural products and drugs, while combinatorial compounds and drugs do not share similar space.

MEDC 603 Fall 2007 23

Natural Products

Current Efforts

CH3

CH3

OH

OH

H

CH3

H CH3

Trinervitane derivative

Nasute termites …. Soldier termites use their nozzle (squirt gun) to tangle up the invader in their toxic glue …. being developed by Entocosm, Australia as an antibiotic …. the natural product is 10 times less potent than a clinically practical antibiotic …. a potent ‘lead’ molecule

S

N

OO

CH3

O

OH

OH

Me

CH3

CH3

CH3

Me Me

Epothilone D

Originally identified through synthesis … epoD was found to be produced by certain bacteria … genetic engineering … polyketide synthase gene knockout (epoD to epoB) … good yields … being developed by Kosan, CA as an antitumor (inhibition of microtubule formation)