Organic Synthesis as a Source of New Drugs - ACS Publications

4 Organic Synthesis as a Source of New Drugs J O H N H . B I E L and Y V O N N E C. M A R T I N

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Experimental Pharmacology Division, Abbott Laboratories, North Chicago, Ill. 60064

The identification teur,

the

concepts

of the infectious

subsequent of selective

the coming

formulation toxicity

of age of organic

disease process by Paul

and rational chemistry

inative

impetus

to the spectacular

which

ushered

in the era of modern

reviews

the evolutionary

synthetic

provided

future

course

viable

factor in the therapy

the

series of drug medicine.

that contributed

to predict

Pas-

of

the

drug design,

process of synthetic

probes the circumstances finally attempts

by

Ehrlich

and imag-

discoveries This

drug

paper

discovery,

to its success,

and

on the basis of current trends

the

drug research of human

must take to remain

a

disease.

^ T * h e p u r p o s e of this c h a p t e r is n o t to g i v e a n exhaustive r e v i e w of s y n A

thetic drugs as t h e y w e r e d e v e l o p e d o v e r the past c e n t u r y , b u t rather

to d e l v e i n t o t h e " a n a t o m y of synthetic d r u g d i s c o v e r y , " p r o b i n g i n t o t h e events that t r i g g e r e d s u c h discoveries a n d t h e c r e a t i v e

reverberations

e m a n a t i n g f r o m t h e m w h i c h gave b i r t h to the m a i n stream of m o d e r n d r u g therapy. P a r t i c u l a r stress is p l a c e d o n the s e q u e n t i a l i n t e r d e p e n d e n c e of cert a i n d r u g fields as w e l l as the i m p o r t a n c e of the state of t h e b i o l o g i c a l art i n r e c o g n i z i n g a d r u g d i s c o v e r y or at least f a c i l i t a t i n g i t . T h u s , t h e major t r a n q u i l i z e r s a n d antidepressants w e r e a synthetic c o n s e q u e n c e of research o n antihistamines w h i c h , i n t u r n , h a d its o r i g i n i n t h e b i o l o g i c a l hypothesis that h i s t a m i n e m i g h t b e the causative agent i n a l l e r g i c responses.

H o w e v e r , the u t i l i t y of t h e p s y c h o t r o p i c drugs w o u l d h a v e gone

l a r g e l y u n n o t i c e d h a d i t n o t b e e n f o r the w i l l i n g n e s s of at least p a r t of t h e p s y c h i a t r i c profession to concede that a " c h e m i c a l " treatment of m e n t a l illness w a s i n d e e d w o r t h y of i n - d e p t h i n v e s t i g a t i o n . T h e " l e i t m o t i f " of this c h a p t e r that b i o l o g i c a l concepts beget synthetic d r u g discoveries w h i c h , i n t u r n , give rise to n e w b i o l o g i c a l discoveries a n d concepts a n d that these exert a p o s i t i v e f e e d - b a c k o n the c r e a t i o n of n e w s t r u c t u r a l d r u g prototypes, is s h o w n s c h e m a t i c a l l y i n F i g u r e 1. 81

In Drug Discovery; Bloom, B., et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1971.

82

DRUG

BIOLOGICAL

DISCOVERY

DISCOVERY

FORMULATION OF A BIOLOGICAL CONCEPT


S T R U C T U R A L PROTOTYPES WITH SUITABLE ACTIVITIES

MOLECULAR MODIFICATION OF PROTOTYPE

OPTIMAL DRUGS IN PARTICULAR THERAPEUTIC A R E A

DISCOVERY OF DRUG ACTION IN OTHER THERAPEUTIC A R E A

FORMULATION OF BIOLOGICAL CONCEPTS RELATIVE TO DISEASE MECHANISM

Figure 1.

Sequence of events leading to synthetic drug discovery

F o r i l l u s t r a t i v e examples w e resorted to those classes of d r u g structures w h i c h s p a w n e d the largest v a r i e t y o f c h e m i c a l t h e r a p e u t i c a r e a s — n a m e l y the s u l f o n a m i d e s , a n t i h i s t a m i n i c s , a n d a d r e n e r g i c

neurotrans-

mitters. B i o c h e m i c a l a n d m o l e c u l a r p h a r m a c o l o g y as those d i s c i p l i n e s w h i c h h a v e a s s u m e d i n c r e a s i n g i m p o r t a n c e i n m o d e r n d r u g d e s i g n c o m p r i s e the last p a r t of this chapter.

Paul Ebrlich's Contribution I n 1899 w h e n P a u l E h r l i c h c a m e face to face w i t h the G e r m a n c h e m i c a l i n d u s t r y a n d s a w the p r o f u s i o n of synthetic a n t i p y r e t i c s , anesthetics, a n d analgetics, h e d e c i d e d that i f it w e r e possible to synthesize substances that d i f f e r e n t i a t e d b e t w e e n v a r i o u s cells i n m a n , i t s h o u l d b e p o s s i b l e to synthesize s i m p l e substances w h i c h w o u l d differentiate b e t w e e n m a n a n d his parasites. F r o m his p u r s u i t of this g o a l w a s b o r n the concept

of selective

t o x i c i t y , receptor theory, side c h a i n theory, i n t r i n s i c a c t i v i t y , a n d affinity. E h r l i c h w a s a p r o p h e t of almost b i b l i c a l p r o p o r t i o n s , a n d m u c h of w h a t h e p r e d i c t e d i n t u i t i v e l y continues to b e c o n f i r m e d e x p e r i m e n t a l l y t h r o u g h


4.

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Organic

A N D MARTIN

83

Synthesis

the a v a i l a b i l i t y of h i g h l y s o p h i s t i c a t e d tools.

T h e fundamental

concepts

w h i c h e v o l v e d f r o m h i s s p e c u l a t i v e t h i n k i n g are s h o w n i n F i g u r e s 2 a n d 3. T h e " b i o l o g i c a l c o n c e p t " ( F i g u r e 2 ) of selective t o x i c i t y s e r v e d as a p o w e r f u l s t i m u l u s n o t o n l y i n the d e v e l o p m e n t of the a n t i m i c r o b i a l a n d i n s e c t i c i d a l d r u g s b u t e v e n m o r e s p e c t a c u l a r l y i n the t h e r a p e u t i c a p p r o a c h to e n d o g e n o u s l y i n d u c e d diseases—i.e., t h e selective i n t e r a c t i o n w i t h cert a i n target tissues w i t h o u t affecting other o r g a n or c e l l u l a r systems.

It

gave rise to a n u m b e r of t h e o r e t i c a l subconcepts w h i c h a t t e m p t e d t o d e a l w i t h d r u g d e s i g n o n a p h y s i c a l c h e m i c a l rather t h a n a p u r e l y i n t u i t i v e Downloaded by UNIV OF ARIZONA on December 11, 2012 | http://pubs.acs.org Publication Date: June 1, 1971 | doi: 10.1021/ba-1971-0108.ch004

or e m p i r i c a l basis.

RECEPTOR T H E O R Y O F D R U G ACTION

7

INTRINSIC ACTION

RECEPTOR AFFINITY

\

RATIONAL DRUG DESIGN

P R E F E R R E D CONFORMATION M O L E C U L A R ORBITAL T H E O R Y HANSCH APPROACH

Figure 2.

Examples of biological concepts that led to considerations in drug design

theoretical

E h r l i c h r e a l i z e d at the outset that a d r u g effect consisted of t w o phases.

F i r s t , i n t e r a c t i o n of c e r t a i n f u n c t i o n a l groups of the d r u g m o l e -

c u l e w i t h specific sites o n the c e l l surface rather t h a n w i t h t h e w h o l e c e l l ; these sites ( r e c e p t o r s ) w e r e so c o n s t i t u t e d as to h a v e a h i g h affinity f o r the prosthetic

groups o f t h e d r u g t h e r e b y

forming a tightly bonded

c o m p l e x . F r o m this a n d L a n g l e y ' s earlier hypothesis e v o l v e d t h e r e c e p t o r t h e o r y w h i c h f o r m e d the basis f o r r a t i o n a l d r u g d e s i g n since

successful

d r u g - r e c e p t o r i n t e r a c t i o n w a s t h o u g h t to b e c a u s e d m a i n l y b y t h e shape ( c o n f o r m a t i o n ) of the p r e s e n t i n g d r u g m o l e c u l e a n d the p h y s i c a l c h e m i c a l forces of a t t r a c t i o n generated b e t w e e n the i n v a d i n g substance a n d the a p p r o p r i a t e c e l l receptor. S e c o n d l y , E h r l i c h r e a l i z e d that the mere i n t e r l o c k i n g of the d r u g w i t h the c e l l receptor w a s n o t sufficient f o r p r o d u c i n g a d r u g effect since b a c teria c o u l d b e stained w i t h o u t b e i n g k i l l e d .

Hence, he postulated not

o n l y a h a p t o p h o r i c ( a n c h o r i n g ) b u t also a t o x o p h i l i c ( p o i s o n i n g ) m o i e t y


84

DRUG

i n the m o l e c u l a r structure of the d r u g .

DISCOVERY

T h e c o m b i n a t i o n of the t h e r a -

p e u t i c agent w i t h the c e l l r e c e p t o r w a s i n itself c o n s i d e r e d harmless b u t s e r v e d to b r i n g the t o x o p h i l i c p o r t i o n of the d r u g close e n o u g h to the c e l l to either p o i s o n i t or p r o d u c e a p h a r m a c o l o g i c effect. F r o m s i m i l a r considerations

A r i e n s a n d v a n R o s s u m d e v e l o p e d , 50 years later,

the

u s e f u l c o n c e p t of affinity a n d i n t r i n s i c a c t i v i t y as d e t e r m i n a n t s of

the

n a t u r e of a d r u g effect. A s e c o n d m a j o r i m p e t u s to m o d e r n d r u g d e v e l o p m e n t c a m e f r o m the d e m o n s t r a t i o n of t h e c h e m i c a l n a t u r e of n e u r o t r a n s m i s s i o n a n d f r o m the Downloaded by UNIV OF ARIZONA on December 11, 2012 | http://pubs.acs.org Publication Date: June 1, 1971 | doi: 10.1021/ba-1971-0108.ch004

i d e n t i f i c a t i o n of h i s t a m i n e as the c h e m i c a l m e d i a t o r i n the p r o d u c t i o n of c e r t a i n a l l e r g i c responses.

A. Albert, "Selective Toxicity"

Figure

3.

Ehrlich's

explanation of immunochemistry symbols, 1898 (35)

T h e results of these t w o approaches discoveries that

in his

own

to d r u g d e s i g n — n a m e l y

the

easily s y n t h e s i z e d o r g a n i c substances c o u l d c u r e

the

diseases c a u s e d b y v i r u l e n t pathogens a n d that m a j o r p h y s i o l o g i c a l p r o c esses a n d responses w e r e u n d e r the c o n t r o l of c h e m i c a l s of s i m p l e structure—came

d u r i n g the p e r i o d w h e n synthetic o r g a n i c c h e m i s t r y

was

u n f o l d i n g to its f u l l b l o o m . It was o n l y n a t u r a l that these three areas of research s h o u l d c o n v e r g e to usher i n the e x c i t i n g a n d u n b e l i e v a b l y p r o d u c t i v e era of m o d e r n synthetic d r u g t h e r a p y . O n e of the results of these early studies w a s the o b s e r v a t i o n d r u g structures

active i n one disease

area w o u l d , t h r o u g h

that

molecular

m o d i f i c a t i o n , y i e l d potent t h e r a p e u t i c agents i n t o t a l l y u n r e l a t e d of p a t h o l o g i c disorders.


fields

4.

BiEL

A N D

MARTIN

Organic

Synthesis

85

The Sulfonamides T h i s g r o u p of d r u g s affords a f a m i l i a r b u t i l l u m i n a t i n g i l l u s t r a t i o n to the m u l t i f a c t e d n a t u r e of d r u g d i s c o v e r y . T h e search b y D o m a g k f o r azo dyes ( b a s e d o n E h r l i c h ' s affinity t h e o r y ) that m i g h t be

(I)

effective

a n t i b a c t e r i a l agents u l t i m a t e l y r e s u l t e d i n 1935 i n the d i s c o v e r y of P r o n t o s i l w h i c h p r o t e c t e d m i c e against l e t h a l streptococcal infections.

Since

this d r u g is i n a c t i v e in vitro, F o u r n e a u , T r é f o u e l , N i t t i , a n d B o v e t tested it i n a r e d u c i n g m e d i u m (2).


findings

T h i s e x p e r i m e n t w a s b a s e d o n E h r l i c h ' s earlier

that p e n t a v a l e n t arsenic h a d to be r e d u c e d to t r i v a l e n t arsenic

in vivo b e f o r e its b a c t e r i c i d a l a c t i o n w a s e v i d e n t . fication,

T h e isolation, identi-

a n d synthesis of the active m e t a b o l i t e , s u l f a n i l a m i d e , p r o d u c e d

a s t r u c t u r a l p r o t o t y p e w h i c h u l t i m a t e l y l e d to major b r e a k t h r o u g h s i n the t h e r a p y of infectious, c a r d i o v a s c u l a r , a n d d i a b e t i c disease ( F i g u r e 4 ). I n a d d i t i o n , other s t r u c t u r a l off-shoots p r o v i d e d a n t i c o n v u l s a n t a n d u r i c o suric drugs. T h e s e successes w o u l d h a v e b e e n i m p o s s i b l e w i t h o u t the c o n c u r r e n t a n d r e q u i s i t e b i o l o g i c a l discoveries. F o r e x a m p l e , the d e v e l o p m e n t of the c a r b o n i c a n h y d r a s e i n h i b i t o r s , w h i c h are u s e d to treat congestive

heart

f a i l u r e , r e s u l t e d f r o m the f o l l o w i n g sequence of b i o l o g i c a l observations: ( 1 ) T h e d e m o n s t r a t i o n of c l i n i c a l acidosis a n d a l k a l i n e u r i n e f o l l o w i n g s u l f a n i l a m i d e a d m i n i s t r a t i o n i n 1937 ( 3 ) . (2)

T h e d i s c o v e r y of c a r b o n i c a n h y d r a s e ( C A ) i n the k i d n e y i n 1941

(4). ( 3 ) T h e i n h i b i t i o n of C A b y s u l f a n i l a m i d e a n d other s u l f o n a m i d e s i n 1940, 1948 ( 5 , 6 ) . ( 4 ) T h e establishment of the r o l e of C A i n the r e a b s o r p t i o n of N a as N a H C 0 a n d d e p r e s s i o n of this f u n c t i o n b y s u l f a n i l a m i d e i n 1945 ( 7 ) . +

3

SULFONAMIDES

ANTIBACT.

DIUR. Figure

4.

HYPOT,

ANTICONV

ANTIDIAB.

URICOSUR.

Schematic representation of the therapeutic evolved from sulfonamide research

areas which


86

DRUG

DISCOVERY

(5) T h e demonstration that sulfanilamide p r o d u c e d increased d i u resis a n d natriuresis i n 1949 (8). T h u s the " r e q u i s i t e b i o l o g i c a l d i s c o v e r y " triggers synthetic d r u g development.

T h e r a t i o n a l i z e d scheme o f this process is s u m m a r i z e d i n

F i g u r e 5. B o t h a m o t i v a t i n g s t i m u l u s a n d a n a d e q u a t e b i o l o g i c a l test are necessary to e n c o u r a g e the m e d i c i n a l chemist to persist i n the sort of synthetic investigations w h i c h finally l e d to the d i s c o v e r y of the t h i a z i d e s b y N o v e l l o , S p r a g u e , B e y e r , a n d B a e r (9, 10, 11).

Similarly, the clinical

o b s e r v a t i o n b y J a n b o n o f the h y p o g l y c e m i c properties of a n i s o p r o p y l Downloaded by UNIV OF ARIZONA on December 11, 2012 | http://pubs.acs.org Publication Date: June 1, 1971 | doi: 10.1021/ba-1971-0108.ch004

t h i a d i a z o l e d e r i v a t i v e of s u l f a n i l a m i d e c a u s e d L o u b a t i è r e s to i n i t i a t e the series of studies w h i c h c u l m i n a t e d i n the d e v e l o p m e n t of t h e s u l f o n y l ureas, a n i m p o r t a n t class of h y p o g l y c e m i c agents. T h u s E h r l i c h ' s o r i g i n a l c o n c e p t that dyes h a v i n g a h i g h i n f f i n i t y for b a c t e r i a c o u l d b e m o d i f i e d s t r u c t u r a l l y to m a k e t h e m b a c t e r i c i d a l

set

off a series of c h e m i c a l a n d b i o l o g i c a l events w h i c h r e s u l t e d i n h e a v y i n r o a d s i n t o some major disease categories.

A testable theory thus r e s u l t e d

i n n e w b i o l o g i c a l i n f o r m a t i o n w h i c h l e d to a s e c o n d testable theory.

The Antihistamines T h e b r i l l i a n t series of researches b y B a r g e r a n d D a l e , D a l e a n d L a i d l a w , a n d L e w i s a n d his colleagues established h i s t a m i n e as the endogenous " n o x i o u s " agent released d u r i n g c e r t a i n types of c e l l injuries a n d h y p e r s e n s i t i v i t y a n t i g e n - a n t i b o d y reactions.

T h e s e observations set

the

stage f o r the b i r t h of the antihistamines a n d h e l p e d to usher i n t h e era of the p s y c h o t h e r a p e u t i c drugs w h i c h h a v e r e v o l u t i o n i z e d the

treatment

of the m e n t a l l y i l l . T h e ease w i t h w h i c h the effects of h i s t a m i n e c o u l d b e d e m o n s t r a t e d i n a n i m a l s a n d i s o l a t e d organs p r o v i d e d a g o l d e n o p p o r t u n i t y for a massive a n d r a p i d screening effort for substances w h i c h w o u l d these actions.

antagonize

B o v e t felt i n t u i t i v e l y that the a m i n o e t h y l side c h a i n i n

h i s t a m i n e was essential f o r c e l l receptor i n t e r a c t i o n a n d p r o c e e d e d select d r u g s w i t h this side c h a i n . H e chose those m o l e c u l e s

to

substituted

w i t h b u l k y p h e n y l groups i n the h o p e that these groups w o u l d s h i e l d t h e receptors f r o m the a p p r o a c h i n g h i s t a m i n e . T h e size of the a l l e r g y m a r k e t a n d the ease of synthesis a n d testing m a d e this a n extremely attractive area f o r research i n m o l e c u l a r m o d i fication.

A s i n the case of the s u l f o n a m i d e s , h i s t a m i n e antagonists p r o -

v i d e d i n r o a d s i n t o disease areas never heretofore

t h o u g h t of as b e i n g

a m e n a b l e to c h e m i c a l attack ( F i g u r e 5 ). T h e sequence of events l e a d i n g to the d i s c o v e r y of these d r u g s is a g a i n r e v e a l i n g . ( 1 ) T h e i s o l a t i o n of a n active endogenous p r i n c i p l e . (2) C h e m i c a l and pharmacologic characterization.


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( 3 ) I d e n t i f i c a t i o n of the noxious agent ( s u b s t a n c e Ή " ) m i n e — i . e . , i d e n t i f i c a t i o n of the p a t h o g e n .

w i t h hista

( 4 ) T h e use of the c o n c e p t of c o m p e t i t i v e i n h i b i t i o n of the h i s t a m i n e receptors as a n a p p r o a c h to the t h e r a p y of a l l e r g y . ( 5 ) M o l e c u l a r d e s i g n a n d m o d i f i c a t i o n to o b t a i n a n o p t i m u m t h e r a p e u t i c response. ( T h e structure of the p a t h o g e n serves as a m o d e l f o r d r u g selection a n d design.)


( 6 ) P r o g r e s s i v e m o l e c u l a r m o d i f i c a t i o n leads to m o d i f i c a t i o n of p h a r m a c o l o g i c response. ( 7 ) T h e state of the m e d i c a l art a n d p h i l o s o p h y o f t h e r a p y h a d a d v a n c e d sufficiently to a l l o w r e c o g n i t i o n a n d e x p l o i t a t i o n (i.e., d i s c o v e r y ) of the t h e r a p e u t i c p o t e n t i a l of the n e w d r u g s b y the " p r i m e d " c l i n i c a l investigator. T h e necessary i n g r e d i e n t s for successful

d r u g d i s c o v e r y are

thus

close i n t e r m e s h i n g of c h e m i s t r y , p h a r m a c o l o g y , a n d c l i n i c a l m e d i c i n e . H o w e v e r , the state of the art i n each d i s c i p l i n e m u s t b e sufficiently a d v a n c e d to a l l o w the simultaneous convergence

of the three d i s c i p l i n e s

t o w a r d the c r e a t i o n of n o v e l t h e r a p y .

ANTIHISTAMINES CNS STIM TRANQUIL.

ANTIALLERG.

ANTIPSYCHOT. Ψ

SEDATIVES

ANTI-PARKIN, Figure 5,

ANTIDEPRESS

ANTI-EMETICS

ANALGETICS

Schematic representation of the therapeutic areas that evolved from research on antihistaminic drugs

The Neurotransmitters as a Source of New Synthetic Drugs U p to this p o i n t r a t i o n a l l y g u i d e d e m p i r i c i s m d o m i n a t e d s y n t h e t i c drug development.

T h e isolation a n d characterization

of

endogenous

substances o f a s i m p l e c h e m i c a l nature, t h e i r i d e n t i f i c a t i o n as

neuro

transmitters of a u t o n o m i c a n d p o s s i b l y c e n t r a l nervous system f u n c t i o n ,


88

DRUG

DISCOVERY

the e l u c i d a t i o n of t h e b i o s y n t h e t i c p a t h w a y s , a n d i s o l a t i o n of t h e enzymes r e s p o n s i b l e f o r t h e i r biogenesis n o t o n l y shed a g o o d d e a l of l i g h t o n the m e c h a n i s m of a c t i o n of existing d r u g s b u t o p e n e d u p greater o p p o r t u n i t i e s f o r r a t i o n a l d r u g design. S u c h substances are s u m m a r i z e d i n F i g u r e 6. D r u g d e v e l o p m e n t i n this area took the p a t h of either p o t e n t i a t i n g , m i m i c k i n g , or inhibiting neurotransmitter action or b l o c k i n g t h e biosyn thetic p a t h w a y s at v a r i o u s steps i n t h e sequence, t h e r e b y e l u c i d a t i n g t h e r o l e of a specific n e u r o t r a n s m i t t e r establishing the dependence Downloaded by UNIV OF ARIZONA on December 11, 2012 | http://pubs.acs.org Publication Date: June 1, 1971 | doi: 10.1021/ba-1971-0108.ch004

their a c t i o n .

i n r e g u l a t i n g nervous f u n c t i o n a n d

of c e r t a i n drugs o n these transmitters f o r

I n a d d i t i o n , t h e m a n i p u l a t i o n of these transmitters

gave

some h i n t as to t h e e t i o l o g y of c e r t a i n disease processes, p a r t i c u l a r l y i n c a r d i o v a s c u l a r , m e n t a l , a n d n e u r o l o g i c a l diseases.

(CH ) NC2H40C-CH 3

3

Acetylcholine

3

0 Ho/

\ — CH(OH) CH N^ 2

H0

Organic Synthesis as a Source of New Drugs - ACS Publications

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