Antiallergic Purinones: A Successful Application of QSAR - American

6 Antiallergic Purinones: A Successful Application of QSAR

Downloaded by CORNELL UNIV on May 18, 2017 | http://pubs.acs.org Publication Date: February 22, 1980 | doi: 10.1021/bk-1980-0118.ch006

K. R. H. WOOLDRIDGE Pharmaceutical Division, May & Baker Ltd., Dagenham, Essex, RM10 7XS, England

When we became interested in the antiallergic field in 1971 at May & Baker, we knew from the studies of Austen et.al. (1) that the inhibition of the anaphylactic release of histamine from human lung could be related to raised tissue levels of cyclic AMP. Furthermore, Lichtenstein and Margolis (2) observed that methylxanthines such as caffeine or theophylline (I) inhibit the antigen-induced release of histamine from human basophilic leukocytes probably by their well-known ability to inhibit phosphodiesterases. We therefore examined the methylxanthines in the passive cutaneous anaphylactic (PCA) reaction mediated by reaginic antibodies in the rat, and found them to be weak inhibitors. They did not inhibit the PCA reaction reactions mediated by non-reaginic antibodies and therefore in this respect the methylxanthines resembled disodium cromoglycate (DSG). Accordingly the xanthines were regarded as a lead to compounds of potential interest for antiallergic therapy, and totally unrelated chemically to DSG. In addition to being weak inhibitors of the rat PCA reaction, the xanthines possess a wide variety of pharmacological properties. Accordingly, available structural variants were examined i n order to improve s e l e c t i v i t y with respect to the PCA inhibition, and to increase potency. Some members of a series of 6-thioxanthines ( i l ) previously studied as bronchodilators (j>) proved to have improved potency (one hundredth of DSG) but this series s t i l l possessed a wide spectrum of pharmacological activity.

0-8412-0536-l/80/47-118-117$05.00/0 © 1980 American Chemical Society

Temple; Drugs Affecting the Respiratory System ACS Symposium Series; American Chemical Society: Washington, DC, 1980.

DRUGS AFFECTING THE RESPIRATORY SYSTEM

118


The introduction of an extra nitrogen into the xanthine system to give 8-azaxanthines had "been reported to reduce cardiovascular effects (4) and we found that 8-azatheophylline ( i l l ) was 10 times more active than the corresponding theophylline or 6-thiotheophylline i n inhibiting the rat PCA reaction whereas the other pharmacological properties were reduced i n magnitude. A series of 8-azaxanthines (IV) were prepared and the best of these compounds was found to be the p-nitrobenzyl derivative (V) which was equiactive with DSG i n the rat PCA test (£).

0H O N0

2

2

(IV)

2

(V)

Application of the multiparameter extrathermodynamic technique to this series, where IL and were alkyl groups, revealed a good relationship between the PCA inhibitory potency (l=relative a c t i v i t y to DSG) and the substituent partition constant (IT) and Taft steric factor (Es) i n the R~ position (equation 1, where the figures i n parentheses are the Student t values for the coefficients of the equation and n, r , s, Ρ and ρ have their usual s t a t i s t i c a l meaning), Eqn. 1

Log /m

- 0.073*T - 0.789 Es (7.00) (4.658) r=0.942, s=0.153f R=3L4 (p < 0.001)

n=11,

Χ ij

= 1.365

2

This relationship was of interest for several reasons. F i r s t l y i t indicated that the biological assay was s u f f i c i e n t l y precise to enable the QSAR approach to be used. Secondly the observation that only alkyl substituents Rp affected the a c t i v i t y whereas alkyl substituents i n the R^ position apparently had l i t t l e influence. This parallels the observations i n the 6-thioxanthine series where a similar relationship was derived for the bronchodilating a c t i v i t y (6)» Thirdly, bulky substituents i n the R position had a beneficial effect. Benzylsubstituted compounds e.g. (v) were more active than equation 1 indicated, possibly because the usual value of Es for benzyl did not r e f l e c t the buttressing effect of the adjacent triazole ring as revealed by a study of space-filling models (£). Other 8-azapurines were tested and an i s o t h i a z o l y l - 8 azapurin-6-one (Vl) exhibited twice the inhibitory potency of DSG. Other heterocyclic-substituted derivatives were no better (2) * ^ 2-phenyl-substituted congener was 4 times as potent as DSG i n inhibiting the rat PCA reaction. 2

l 3 U

η θ


6.

119

Antiallergic Purinones

wooLDWDGE

1

H


(m) A series of substituted 2-phenyl-8-azapurin-6-ones (VIl) was prepared (Table 1) and when the results on the f i r s t 10 compounds was available, correlations were sought between the inhibitory a c t i v i t y and electronic, steric, and partition parameters, but without success. However the results on the azaxanthines (equation 1) suggested that bulky substituents might lead to increased a c t i v i t y and this was supported i n the phenylazapurinone series by the higher a c t i v i t y of the orthomethoxy compound (Table 1, No. 4) as compared with the meta (No. 8) and para (No. 10) isomers. However the prjfep-methyl Table 1 The inhibitory a c t i v i t y i n the rat PCA reaction of substituted 2-phenyl-8-azapurin-6-ones relative to DSG following i . v . admini s tration

V Ν

IT ιτ

R Compound No.

H

2

h ï ï

Relative Activity (DSfel) 4.0

Subst.

1

-fy

2-CH

5

2-C1

Es

a

1.24

0.04

0

b V

Obs Log

Calc Lo£ /fit y x

α®*

x

0 16

2.932 0.959

l7

2.743 1.111

0.2

0.27

17

1.695

1.519

10.0

0.69

108

3.586

3.201

5.0

0.69

128

5.152

3.435

2

10.0

0.69

121

5.504

3.353

7

5-CH

4.0

1.24

0

2.959

2.743

8

3 3-CHÔ

2.0

1.24

0

2.687

2.743

2.0

1.24

0

2.695

2.743

0

2.586

2.743

55

2-GHjO

4 5

2-1-0^0

6

2-C H CH 0 6

5

5

4-C1

9

4-CH,0

10

1.0

1.24

^SrrTaft* s steric factor of the 2-substi tuent b —I Difference ) between the with 1-NH compound stretching1, frequency i n the substituted (cnT compound compared f

Equation 2



120

compound (No. 2) showed only 1/100 of the a c t i v i t y of the meta isomer (No. 7) suggesting very strongly that other factors must be involved. Intramolecular hydrogen bonding between the proton i n the 1-N position and the ortho substituent i n the phenyl ring could be involved; and fortunately this could readily be quantified by comparison of the NH-stretching frequency i n the substituted compound compared with the parent compound (No. 1 ) . This i r s h i f t , ûv, may be regarded as an energy term and when i t was used as a parameter i n regression analysis, a highly significant relationship, equation 2 was obtained ( 8 ) . Log /ÏW Χ I? = 0.924 + 0.012 Δ ν + I.467 Es (7.50) (7.72) n=10, r = 0 . 9 6 l , s=0.244, P=42.7, Ρ < 0 . 0 0 1 . As the Es term decreases i n numerical value with increasing size of the substituent, equation 2 indicated that antiallergic a c t i v i t y i s increased by high hydrogen bonding and decreased by increasing size of the ortho substituent i n the phenyl ring. The knowledge of the relevant factors rapidly led us to synthesise the most active member of the series, the orthopropoxy compound, M&B 22,948 (VIIl), about 40 times as potent as DSG (2)·


Eqn. 2

(VIII)

(IX)

(X)

We interpreted the relationship i n equation 2 to mean that coplanarity of the phenyl ring with the azapurinone system i s a requirement f o r hi^hL antiallergic a c t i v i t y i n the test system employed. Hydrogen bonding with a suitable ortho substituent i n the phenyl ring would favour planarity while a bulky substituent would reduce planarity. A c t i v i t y would be maximised by a high degree of hydrogen bonding coupled with small size. Simple ether substituents as i n MScB 22,948 appear to be optimal i n this respect. Additional evidence i s provided by the fact that the a c t i v i t y of the 2-pyridyl analogue (IX) which does not show intramolecular hydrogen bonding i s increased over 100-fold by formation of the N-oxide (x) which forms exceptionally strong intramolecular hydrogen bonds. This coplanarity hypothesis o r i g i n a l l y deduced from the QSAR equation has been substantiated by some recent work i n which M&B 22,948 has been shown to be planar i n the solid state by X-ray crystallography (10). In addition to causing 100% inhibition of the rat PCA reaction following intravenous administration at 0.1 mg/kg, M&B 22,948 was also active orally. When administered to rats



6.

wooLDRiDGE

Antiallergic

121

Purinones

15 minutes before allergen challenge, i t was effective i n inhibiting the PCA reaction at doses of 0 . 5 - 2 mg/kg with a b e l l shaped dose response curve. This compound also inhibited the allergen-induced release of histamine and SRS-A from passively sensitised human lung tissue i n v i t r o , and inhibited reaçinmeditated anaphylactic bronchospasm i n the guinea pig (£7· Toxicological studies i n several species have been satisfactory and the compound i s effective i n man following administration i n doses of 5-15 uag "by aerosol administration. Further substitution i n the alkoxyphenyl-8-azapurinones gave a series of compounds i n which the hydrogen bonding did not vary appreciably but i n which the antiallergic potency spanned a wide range (Table 2). The a c t i v i t y correlated with the substituent partition value τ f o r the 5-position as the dominant parameter, with a smaller contribution from the resonance factor R defined by Swain and Lupton (Vl) equation 3· 9

Log /mi Χ τ/ = 3·57 - 0.74 + 0.87 R (6.40) (2.79) n=9, r=0.940, s=0.205, P=22.9, Ρ < 0.01

Eqn. 3

Table 2 The inhibitory a c t i v i t y i n the rat PCA reaction of 5-substituted 2-methoxyphenyl8-azapurin-6-ones Η

Compound No.

Subst.

4

Η

11

N0

Relative Activity (DSG=1) 10

IT 0

p

11

0

Obs Log:

Calc LOJ

3.384

3.569

10

-0.28

0.155 3.459

3.909

MH

40

-I.23

-0.681 4.029

3.885

13

HO

10

-0.67

-Ο.643 3.413

3.506

14

CHjO

4

-0.02

-O.5OO 3.038

3.151

12

2

2

15

10

0.56

-O.HI 3.410

3.064

4

0.88

0.186 3.095

2.942

16

CP

17

CI

2

0.71

-0.161 2.745

2.907

18

t-Bu

0.5

1.83

-0.138 2.176

2.213

3

This equation suggested that electron-withdrawing hydrophilic substituents should be highly active i n this test system, and as a result a number of such compounds were prepared.



122

Many of these compounds i n fact proved to "be highly potent (Table 3) and provide an example of the predictive use of multiparameter regression analysis, (lj2) although the analysis of the f u l l series, which i s s t i l l i n progress, suggests that equation 3 i s an over-simplification (15)· Table 5 5-Substituted 2-alkoxyphenyl-8-azapurines with predicted high activity


Orι « , .. . , Substituent

R

Predicted A c t i v i t y * ( 3 ) S f c l )

Observed A c t i v i t y ( 3 ) S G = 1 )

SO^

336

150

SOê

138

200

63

200

18

40

C0M

2

COê •Êquation 3

Work on this series was i n i t i a t e d on the supposition that inhibition of phosphodiesterase would increase the level of cyclic AMP thereby leading to antiallergic effects. Subsequent work i n our laboratories has suggested that this was a gross oversimplification. Using 25 known antiallergic agents of widely varied chemical structural features, we have shown that the more potent inhibitors of anaphylactic reactions i n h i b i t the hydrolysis of c y c l i c GMP more effectively than that of c y c l i c AMP. The implication i s that histamine release i s reduced more effectively when cyclic GMP levels are increased with respect to cyclic AMP levels. The fact that highly significant correlations were obtained between selective inhibition of phosphodiesterase a c t i v i t y and pharmacological potency i n i n v i t r o and i n vivo tests involving different species and different tissues may well r e f l e c t a basic common mechanism of fundamental importance i n a l l e r g i c reactions (14)» However, the azapurines i n vivo show the bell-shaped doseresponse curves i n antiallergic tests, typical of DSG-like compounds but unlike phosphodiesterase inhibitors. I t i s possible, therefore, that the antiallergic a c t i v i t y of the azapurines i s due to a combination of mast c e l l stabilisation and phosphodiesterase inhibition.


6.

WOOLDRiDGE

Antiallergic Purinones

123


LITERATURE CITED 1.

Orange, R.P., Kaliner, M.A., Laraia, P.J. and Austen, K.F. Fed.Proc., (1971), 30, 1725.

2.

Liechtenstein, L.M. and Margolis, S. Science, (1968), 161, 902.

3.

Wooldridge, K.R.H. and Slack, R. J.Chem.Soc., (1962), 1863.

4.

Bariana, D.S. J.Med.Chem., (1971), 14, 543.

5.

Coulson, C.J., Ford, R.E., Lunt, Ε., Marshall, S., Pain, D.L., Rogers, I.H. and Wooldridge, K.R.H. Eur.J.Med.Chem., (1974), 9, 313.

6.

Bowden, K. and Wooldridge, K.R.H. (1973), 22, 1015.

7.

Holland, Α., Jackson, D., Chaplen, P., Lunt, Ε., Marshall, S., Pain, D.L. and Wooldridge, K.R.H. Eur.J.Med.Chem., (1975), 10, 447.

8.

Broughton, B.J., Chaplen, P., Knowles, P., Lunt, Ε., Marshall, S., Pain, D.L. and Wooldridge, K.R.H. J.Med.Chem., (1975), 18, 1117.

9.

Broughton, B.J., Chaplen, P., Knowles, P. Lunt, E., Pain, D.L., Wooldridge, K.R.H., Ford, R., Marshall, S., Walker, J.L. and Maxwell, D.R. Nature (London), (1974), 251, 650.

Biochem.Pharmacol.,

10.

Hodgson, D. (University of North Carolina) unpublished work.

11.

Swain, C.G. and Lupton, E.C. 90, 4328.

12.

Ford, R.E., Knowles, P., Lunt, Ε., Marshall, S., Walker, J.L. and Wooldridge, K.R.H. Unpublished.

13·

Coombs, T.J. and Wooldridge, K.R.H. Unpublished.

14.

Bowden, K., Coombs, T . J . , Coulson, C.J., Ford, R.E., Marshall, S., Walker, J.L. and Wooldridge, K.R.H. Nature (London), (1977), 265, 545.

RECEIVED

J.Amer.Chem.Soc., (1968),

August 6, 1979.


Antiallergic Purinones: A Successful Application of QSAR - American

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