The Development of Antiallergic Pyranenamine Series: A QSAR

9 The Development of Antiallergic Pyranenamine Series: A QSAR Success Story

Downloaded by UNIV ILLINOIS URBANA on May 2, 2013 | http://pubs.acs.org Publication Date: February 22, 1980 | doi: 10.1021/bk-1980-0118.ch009

RICHARD D. CRAMER III, K E N N E T H M. SNADER, CHESTER R. WILLIS, LAWRENCE W. CHAKRIN, JEAN THOMAS, and BLAINE M. SUTTON

Research and Development Division, Smith Kline and French Laboratories, Philadelphia, PA 19101 Quantitative Structure-Activity Relationships (QSAR) express the biological potencies of a series of related compounds as a linear function of their physicochemical properties. A major reason for deriving a QSAR hypothesis is the hope that some aspect of the QSAR can be successfully extrapolated, to produce compounds of potency higher than any of those from which the QSAR was derived. Unfortunately, the QSAR literature does not contain many examples of successful extrapolation, or "predictive successes. "(1) Even these few examples would be vulnerable to the following criticisms: (1) The successful extrapolations are relatively small in magnitude, the potency enhancement in only one instance(2) being appreciably more than twofold. (2) The actual number of superior compounds associated with each individual successful extrapolation is rather small. (3) Alternative but simpler physicochemically based strategies, such as the "Topliss tree"(3), seem to point to superior compounds and require far less work. (4) "Sooner or later" the compounds embodying the successful extrapolations would have been stumbled upon in any case. (Of course, actual medicinal chemistry programs have finite lifetimes, dependent in part on their own success, such that a "later" which is insufficiently "sooner" may become a "never"!) In view of these criticisms, we suggest that the development of the pyranenamine series represents one of the more clearcut successes in the application of QSAR techniques. To provide substance for this claim, in this article we have elected to present the pyranenamine series development in a strictly chronological fashion. Overall Considerations. As described in detail within the preceding articled J, the pyranenamines display Intal-like anti0-8412-0536-l/80/47-118-159$05.00/0 © 1980 American Chemical Society

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

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a l l e r g i c p r o p e r t i e s i n a w e l l - e s t a b l i s h e d experimental animal model, the passive cutaneous anaphylactic (PCA) r a t . In t h i s study, we w i l l be concerned only with the e f f e c t s of changes i n the aromatic s u b s t i t u e n t s -X, -Y, and -Z upon potency i n the PCA model.


X

An unfavorable c h a r a c t e r i s t i c of these b i o l o g i c a l data i s r e l a t i v e l y high v a r i a b i l i t y . The most s e r i o u s v a r i a b i l i t y occurs f o r a group of twenty compounds which d i s p l a y e d no a c t i v i t y at the t e s t i n g dose. Such compounds were simply assigned a Ρ Ι 5 0 one u n i t l e s s than log (1/dose t e s t e d ) . The standard e r r o r f o r such an assignment i s of course unknowable, i f one assumes a value of +·9, the RMS e r r o r f o r the o v e r a l l c o l l e c t i o n of 98 potency measure ments would be roughly +.48. This value i s to be compared with S, the standard e r r o r of a r e g r e s s i o n . If S i s greater than .5 0, the s t i l l unexplained d i f f e r e n c e s i n compound potency are greater than those a t t r i b u t a b l e to b i o l o g i c a l v a r i a b i l i t y and thus a d d i t i o n a l s t r u c t u r a l explanations of the data may be sought. But once S has dropped below t h i s estimated net b i o l o g i c a l v a r i a b i l i t y of 0.5, there i s an i n c r e a s i n g danger that apparent s t r u c t u r a l trends may i n f a c t only be a r t i f a c t s o r i g i n a t i n g i n the b i o l o g i c a l v a r i a b i l ity. The parameters and methods employed i n r e g r e s s i o n studies of the pyranenamine s e r i e s have been discussed elsewhere, along with complete r e s u l t s . "Pre-Qsar" S e r i e s Development. Potency (Log 1/c) values f o r the f i r s t nineteen pyranenamines to be synthesized and tested i n the PCA assay, p r i o r to the use of QSAR i n t h i s s e r i e s , appear i n part A of Table I. The majority of these d e r i v a t i v e s were syn t h e s i z e d i n response to a newly proposed (at that time) d e c i s i o n model, the T o p l i s s operation scheme or " t r e e " . Q ) . Based on the observation that physicochemically-based s u b s t i t u e n t constants are an aspect of the Hansch approach which i s e a s i e r f o r s y n t h e t i c a l l y o r i e n t e d chemists to a s s i m i l a t e than i s r e g r e s s i o n a n a l y s i s , T o p l i s s proposed s p e c i f i c sequences of s u b s t i t u t e d d e r i v a t i v e s to be synthesized, with the next choice at each s e q u e n t i a l step being governed by whether the preceding compound d i s p l a y e d e i t h e r i n creased, decreased, or unaltered potency. Retrospective s t u d i e s


CRAMER E T A L .

9.

Table I:


A.

ÇSAR

Potencies of Pyranenamines Synthesized Been E s t a b l i s h e d .

Substituent

Ρ 50

H 2-C1 3-C1 4-C1 4-F 4-N0 4-C00Me 4-Me 2-OH 3-OH 4-OH 4-0Me 2-NH 4-N(Me) 4-pyridyl 3,4-Cl 3,5-CF 2,6-Cl 2,6-OH

- .7 -1.2 - .7 - .6 -1.0 -2.0 -1.7 -1.2 - .4 - .2 - .1 - .9 -1.4 -2.0 - .9 -2.0 -1.1 -2.0 - .7

2

2

3

χ

B i o i o s t e r e s and Prodrugs of the 4-0H D e r i v a t i v e Substituent

P*50

4-0C0Me 4-0C0Et 4-0C0(n)Pr 4-0C0(n)Bu 4-0C0(n)Am 4-0C0(n)Hex 4-0C0(t)Bu 4-0C0Ph 4-0C0NH 4-0C0NHCH Ph 4-0CH C00H 4-SH 4-NH 4-NHCH0

+ .2 - .1 - .2 + .2 -1.1 + .0 - .7 - .7 + .0 + .0 + .3 - .2 + .4 + .3

2

2

2

2

a

Before QSAR Had

Pyranenamines Used i n D e r i v a t i o n of the F i r s t QSAR

2

Β.

161

Development of Pyranenamines

Rationale

3

3 3 3 3 3 3 3 3 3 3 3 3 2 2

Codes the r a t i o n a l e f o r s y n t h e s i s : 1 = QSAR; 3 = c l a s s i c a l m e d i c i n a l chemistry; 2 = both. See Discussion.



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indeed suggest that use of the " T o p l i s s t r e e " might halve the number of d e r i v a t i v e s needed to achieve an optimal potency. In the pyranenamine s e r i e s , choice among the "next" appropriate d e r i v a t i v e s had been made d i f f i c u l t by experimental u n c e r t a i n t y surrounding the r e l a t i v e potency values, and as a r e s u l t Table I contains information about most of the nodes i n the " T o p l i s s t r e e " , not merely an i n d i v i d u a l branch. In f a c t , the 4-OH d e r i v a t i v e , the most potent of the nineteen, can be reached v i a the t r e e only by taking the apparent "wrong turn" at two of three nodes. S t r i c t adherence to the d e c i s i o n model would have produced nothing but d e r i v a t i v e s l e s s a c t i v e than the s t a r t i n g u n s u b s t i t u t e d compound. As the most promising member of the pyranenamine s e r i e s , by the o r a l as w e l l as the intravenous route of a d m i n i s t r a t i o n , SK&F 64398 was s e l e c t e d f o r d e t a i l e d b i o l o g i c a l e v a l u a t i o n . Meanwhile, f o l l o w i n g well-known precepts, a v a r i e t y of d e r i v a t i v e s and c l o s e congeners ( " b i o i s o s t e r e s " ) of SK&F 64398 were prepared f o r t e s t i n g i n the PCA assay. The subsequent t e s t i n g r e s u l t s , shown i n Part Β of Table I, might be summarized as suggesting that the t r a d i t i o n a l " c l o s e analogue" s t r a t e g y y i e l d e d compounds which were e q u i v a l e n t , but not markedly s u p e r i o r , i n potency to SK&F 64398. In the absence of the QSAR studies to be d e s c r i b e d i t might w e l l have been reasonable to conclude that SK&F 64398 i s f o r p r a c t i c a l pur poses the "optimal" pyranenamine, and that the s y n t h e t i c program which produced i t had been s u c c e s s f u l l y completed. I n i t i a l QSAR Studies. The challenge posed f o r QSAR study was c l e a r l y , " W i l l a n a l y s i s of the nineteen data shown i n Part A of Table I produce any s t r u c t u r e / a c t i v i t y trends whose e x t r a p o l a t i o n seems l i k e l y to suggest pyranenamines having potency s i g n i f i c a n t l y g r e a t e r than that of SK&F 64398?" The nineteen compounds by v i r tue of t h e i r d i f f e r e n t s u b s t i t u e n t s have d i f f e r i n g p h y s i c a l prop erties. The observed d i f f e r e n c e s i n b i o l o g i c a l p r o p e r t i e s can u l t i m a t e l y be caused only by these d i f f e r e n c e s i n p h y s i c a l prop e r t i e s , according to a l l known f a c t s of biochemistry and p h y s i o l ogy. However, biochemistry and physiology a l s o teach that the mechanisms through which these d i f f e r e n c e s i n p h y s i c a l p r o p e r t i e s might express themselves, i n c l u d i n g metabolism and d i s t r i b u t i o n as w e l l as the mechanics of i n t e r a c t i o n with the "receptor", may be so complex as to preclude the establishment of u s e f u l trends. These c o n s i d e r a t i o n s of course have been more or l e s s c o n s c i o u s l y recognized by every p a r t i c i p a n t i n m e d i c i n a l chemistry research throughout i t s h i s t o r y . Reason demands an attempt to understand one's data but experience soon suggests that such an attempt w i l l produce nothing more u s e f u l than post hoc r a t i o n a l i z a t i o n s . I n i t i a l a n a l y s i s of the data i n Table IA was c a r r i e d out g r a p h i c a l l y , by p l o t t i n g l o g (1/C) values f o r the nineteen com pounds against measures of t h e i r physicochemical d i f f e r e n c e s , s p e c i f i c a l l y measures of s i z e (molar r e f r a c t i v i t y ) , a f f i n i t y f o r p o l a r s o l v e n t s ( π ) , and i n t r a m o l e c u l a r e l e c t r o n i c e f f e c t (σ).



9. CRAMER ET AL.

QSAR Development of Pyranenamines

163

The most promising of the various graphs was the "three-dimen s i o n a l " p l o t shown i n Figure I· This p l o t portrays potency, p l o t t e d along the C a r t e s i a n a x i s perpendicular to the page as a j o i n t f u n c t i o n of π and σ, where as an a i d i n o r i e n t a t i o n the l o c a t i o n i n π/σ space of most common s u b s t i t u e n t s a l s o are indicated.^-) To help i n communicating the dependence of potency on π and σ which was v i s u a l i z e d as the graph was constructed, potency contour l i n e s were a l s o sketched i n . Thus the completed graph shows potency as a h y p o t h e t i c a l f u n c t i o n of π and σ i n the same manner that a conventional r e l i e f map shows ground e l e v a t i o n as a f u n c t i o n of longitude and l a t i t u d e . The apparent "peak" i n the potency/π/Δ map i s l o c a t e d j u s t below the center of i t s l e f t - h a n d edge, corresponding to s u b s t i tuents possessing a combination o f high h y d r o p h i l i c i t y and n e g l i g i b l e intramolecular e l e c t r o n i c influence. I f the r e l a t i o n s h i p s suggested by the graph are a c o r r e c t model of the behavior of sub s t i t u t e d pyranenamines i n the PCA r a t , s u b s t i t u e n t s c o n f e r r i n g even g r e a t e r h y d r o p h i l i c i t y should improve potency f u r t h e r , pro vided that the o v e r a l l e l e c t r o n i c character i s not thereby d i s turbed. Unfortunately, the promising area of Figure I i s very s p a r s e l y populated by a c t u a l s u b s t i t u e n t s , only -NHCONH2 and -NHOH being barely w i t h i n the region of i n t e r e s t . To o b t a i n substan t i a l l y increased h y d r o p h i l i c i t y without e l e c t r o n i c e f f e c t s , pyranenamines having p a r t i c u l a r combinations of s u b s t i t u e n t s were proposed as s y n t h e t i c t a r g e t s . Two of the twelve targets were synthesized immediately and found to be h i g h l y a c t i v e , a 3-acetamide-4-hydroxyl d e r i v a t i v e having a PI50 o f +0.8, or a potency 2-1/2 times greater than any of the other pyranenamines and the isomeric 2-hydroxy-5-acetamido d e r i v a t i v e a ΡΙ50 o f +0.2, second only to the 4-NH2 congener. This s t r i k i n g confirmation of the " h y d r o p h i l i c i t y hypothesis" l e d to a strong emphasis on h y d r o p h i l i c s u b s t i t u t i o n patterns i n en suing work. Development o f the H y d r o p h i l i c i t y Lead. Because of the ease of s y n t h e s i z i n g and t e s t i n g pyranenamines, i t was p o s s i b l e to evaluate the e f f e c t s of an unusually l a r g e v a r i e t y of types and combinations of h y d r o p h i l i c s u b s t i t u e n t s . From a physicochemical point o f view, while increased h y d r o p h i l i c i t y was the primary o b j e c t i v e i t was a l s o recognized that e x p l o r a t i o n of a broader c l a s s o f s u b s t i t u e n t s might uncover dependencies on parameters other than π and σ. From a more conservative point of view, whether or not the t e n f o l d potency conferred upon the 4-0H d e r i v a t i v e by adding a 3-acetamido s u b s t i t u e n t r e l a t e s a t a l l to increased h y d r o p h i l i c i t y , the magnitude of the r e s u l t i n g i n c r e a s e mandates f u r t h e r e x p l o r a t i o n of a t r a d i t i o n a l nature, such as removal of the 4-0H, lengthening and shortening of the acylamido c h a i n , transposing or a l t e r i n g the s u b s t i t u e n t s , or i n t r o d u c i n g additional substituents. The a c t u a l compounds chosen f o r syn t h e s i s n a t u r a l l y tended to be c o n s t r u c t i v e i n terms of e i t h e r


DRUGS A F F E C T I N G T H E RESPIRATORY


164


SYSTEM

CRAMER ET

9.

AL.

ÇSAR


165


of these two points of view, and thus only a m i n o r i t y of the seventy-odd compounds remaining to be discussed bear unambiguously on the issue of whether the QSAR approach continued to enhance the e f f i c i e n c y of pyranenamine s e r i e s development. The Value of Regression A n a l y s i s . Once we had conceded the p o s s i b i l i t y that more than the two v a r i a b l e s π and σ might be i n f l u e n c i n g PCA r a t potency, the g r a p h i c a l approach exemplified i n Figure I had to be abandoned, despite i t s ease of construc t i o n and c l e a r p o r t r a y a l of the postulated s t r u c t u r e / a c t i v i t y relationship. In a d d i t i o n to the obvious i m p o s s i b i l i t y of p o r t r a y i n g more than three v a r i a b l e s on a two-dimensional graph, the time required to construct graphs having more than, say, t h i r t y points i s much greater than that to perform equivalent r e g r e s s i o n s . A f u r t h e r bonus i n using r e g r e s s i o n techniques i s that the accompanying s t a t i s t i c a l i n d i c e s ( r , s, and F) allow an assessment of the p r o b a b i l i t y that the SAR i s " r e a l " , J..e^., not a chance ordering of information which i n r e a l i t y i s unrelated. No o b j e c t i v e response would have been p o s s i b l e to a c r i t i c who doubted the r e a l i t y of the " h i l l " portrayed i n Figure I. A r e g r e s s i o n equation c o n t a i n i n g very much the same informa t i o n as that contained i n Figure I, and d e r i v e d from the data i n Table I, w i l l be r e f e r r e d to subsequently as A: pl r

2

5 0

= - .72 - .14(+.29) χ Σττ — 1.35(+.98) χ

= .48

s = .47

F(2,16) =

(Σσ)

2

7.3

The equation has two structurally-dependent terms, conforming to the two dimensions of the graph i n Figure I. The negative co e f f i c i e n t of i t s π term describes an increase i n potency with decreasing l i p o p h i l i c i t y equivalent to the r i g h t - t o - l e f t upward slope of the " h i l l " i n Figure I. The negative c o e f f i c i e n t of the σ term connotes a potency which i s maximal when σ = 0 and de creases as σ deviates markedly above or below 0. This d e s c r i p t i o n of e l e c t r o n i c e f f e c t s d i f f e r s s l i g h t l y from that of Figure I where the apparent "optimal" σ i s l e s s than 0. In a r e g r e s s i o n equation a non-zero, i n t h i s instance negative, value f o r the optimal σ would r e q u i r e two terms f o r i t s expression ( -aa - b σ ) . The a d d i t i o n a l term produced by entry of σ i n t o Equation A indeed possesses a negative c o e f f i c i e n t but has very low s t a t i s t i c a l significance. P a r e n t h e t i c a l l y , i t might be thought that t h i s type of p l o t i n p r i n c i p l e o f f e r s the p o s s i b i l i t y of d e t e c t i n g non-linear or non-parabolic r e l a t i o n s h i p s between potency and π or σ, r e l a t i o n ships which might not be well-approximated by a n a l y t i c functions of ι or σ and hence would be undetectable by r e g r e s s i o n . The idea that a complex but continuous f u n c t i o n a l r e l a t i o n s h i p might e x i s t between π or σ and b i o l o g i c a l a c t i v i t y has a l s o been c i t e d i n recommending o p t i m i z a t i o n techniques such as the Simplex method 2

2


DRUGS A F F E C T I N G

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T H E RESPIRATORY

f o r drug design p r o b l e m s ^ ) . Nevertheless, we f e e l that an extensive search f o r such more mathematically complex r e l a t i o n ships i n v o l v i n g simple physicochemical p r o p e r t i e s i s probably wasted e f f o r t . From a p r a c t i c a l point of view i t i s almost e x c l u s i v e l y the l i n e a r r e l a t i o n s h i p s between a c t i v i t y and a s t r u c t u r a l v a r i a b l e which seem l i k e l y to be e x t r a p o l a b l e i n a u s e f u l way. A s t r u c t u r a l dependency which already contains a w e l l - d e f i n e d optimum o f f e r s l i t t l e hope and only negative guid ance i n the quest f o r improved potency! The s t a t i s t i c a l q u a l i t y of equations i s i n d i c a t e d by t h e i r values f o r r , s, and F. To an e x c e l l e n t approximation, r measures the proportion of the o r i g i n a l d i f f e r e n c e s i n compound potency which are explained by the r e g r e s s i o n equation, whereas i n c o n t r a s t s measures the absolute d i f f e r e n c e s i n potency which are not explained by the r e g r e s s i o n equation. Thus r and s are complementary i n d i c e s , while F, a r a t i o of r to s weighted by the number of degrees of freedom f o r each, allows an assessment of the l i k e l i h o o d of achieving a c o r r e l a t i o n as good or b e t t e r by chance alone. Oddly, a concise statement of these p r i n c i p l e s seems ab sent from the QSAR l i t e r a t u r e , r e s u l t i n g i n a c e r t a i n amount of apparent confusion among some of i t s p r a c t i t i o n e r s over what the s t a t i s t i c a l o b j e c t i v e of a r e g r e s s i o n a n a l y s i s should be. Since one should never expect s to be much l e s s than the experimental v a r i a b i l i t y of the b i o l o g i c a l measurements, the only way a high r can r e a l i s t i c a l l y be expected i s i f the experimental v a r i a b i l i t y i s very low or i f the range of b i o l o g i c a l potencies i s very l a r g e . As w i l l be seen, the r e g r e s s i o n equations h e r e i n i l l u s t r a t e these points rather w e l l . In p a r t i c u l a r , the unusually poor value of r f o r Equation A, .46, i s a c t u a l l y about as high as one might hope to achieve with the data of Table I, since the e s t i mated experimental v a r i a b i l i t y of .5 f o r the o v e r a l l data set i s i n f a c t somewhat greater than the s f o r Equation A. Despite the low r , comparison of the F(2,16)=7.3 with i t s tabulated values shows that the l i k e l i h o o d of o b t a i n i n g a c o r r e l a t i o n even t h i s poor by chance alone f o r two parameters a c t u a l l y unrelated to potency and nineteen compounds i s l e s s than 1%. 2


SYSTEM

2

2

2

2

2

2

Second Phase; E x p l o r a t i o n of Other H y d r o p h i l i c Groups; The l a r g e v a r i e t y of h y d r o p h i l i c groups explored i n what might be r e garded as the second phase of the QSAR development of the pyranenamine l e a d are l i s t e d i n Table I I . Several f e a t u r e s of these data are p a r t i c u l a r l y i n c o n s i s t e n t with the hypothesis that b i o l o g i c a l potency depends s o l e l y on π and on σ: 1) The e x c e p t i o n a l l y high potency of the 3,5-NHCOMe d e r i v a t i v e , an order of magnitude greater than any other s e r i e s member, despite unremarkable π and σ values, suggests that there must be other compound property(s) capable of enhancing potency. 2) The potencies of the i n c r e a s i n g l y l i p o p h i l i c 3-NHCOMe, 3-NHCOEt, and 3-NHCOPr subseries would be expected to


9.

ÇSAR

CRAMER E T A L .

167


Table I I ; Potencies of Compounds Synthesized A f t e r Development of the F i r s t QSAR (Equation A ) . Substituent

P*50

3-S0 NH 4-S0 NH 3-NH 2-NHCHO 3-NHCHO 2-NHCOMe 3-NHCOMe 4-NHCOMe 3-NHCONH 4-NHCONH 3-NHCOEt 4-NHCOEt 3-NHC0(i)Pr 4-NHC0(i)Pr 3-NHC0(n)Pr

+ + + + + + + + + +

2

2

2

2


2

2

2

.3 .1 .5 .3 .7 .7 .7 .7 .3 .2 .7 .2 .5 .4 .4

Rationale

3

1 1 2 2 2 2 2 2 1 1 2 2 2 2 2

,COCH

2

3-N

+ .0 COCH

2

3-NHS0 Me 4-NHS0 Me 3-NHS0 Ph 4-NHS0 Ph 3-NH -4-OH 3-NHCCMe-4-OH 3,4-N=CMe-03-NHCQMe-4-0Me 3-NHCOEt-4-OH 3-NHCO(i)Pr-4-OH 3,5-NHCOMe 3,5-NHS0 Me 3-NHC0Me-6-OH 2

2

2

2

2

2

a

+ .1 - .7 - .1 - .7 + .15 + .7 - .1 + .1 + .4 + .7 +1.9 + .5 + .2

2 2 2 2 2 1 3 3 2 2 2 2 1

Codes the r a t i o n a l e f o r s y n t h e s i s : 1 = QSAR; 3 = c l a s s i c a l medicinal chemistry; 2 = both. See Discussion.


DRUGS

168

AFFECTING

T H E RESPIRATORY

SYSTEM

d e c l i n e , rather than remain constant, i n the absence of a d d i t i o n a l trends. S i m i l a r l y , although l e s s s i g n i f i c a n t l y because of a pro-drug p o s s i b i l i t y , the 0-CO-R d e r i v a t i v e s are equipotent d e s p i t e representing a very l a r g e range of l i p o p h i l i c i t i e s . These observations appear to be s a t i s f a c t o r i l y explained by Equation B, derived from a l l data i n Tables I and II except f o r e x c l u s i o n of the 4-OCH2COOH s u b s t i t u e n t because of the s t r u c t u r a l ambiguity introduced by i t s two p o s s i b l e protomeric forms.


pl

r

2

5 0

- - .75

= .77

2

-.30(+.12) χ Σττ — 1.5(+.67) χ ( Σ σ ) + 2.0(+2.0) χ F-5 + .39(+.22) χ //345-HBD - .63(+.33) χ //NHS02 + .78(+.46) χ M-V + .72(+.31) χ 4-0C0?

s = .40

F(7,53) = 25.1

L i p o p h i l i c i t y , a s t a t i s t i c a l l y dubious c a u s a t i v e f a c t o r i n Equation A although apparently important i n the l o g i c a l l y equiv a l e n t Figure I, has with the a d d i t i o n a l data emerged as the dominant s t r u c t u r a l i n f l u e n c e on potency. At t h i s point i n s e r i e s development, s u b s t i t u e n t l i p o p h i l i c i t y spanned a range of four l o g u n i t s , potency doubling with each l o g u n i t increase i n h y d r o p h i l i c i t y . Many more l o g u n i t s of s u b s t i t u e n t h y d r o p h i l i c i t y were s t i l l p o t e n t i a l l y a c c e s s i b l e , most r e a d i l y by employing charged s u b s t i t u e n t s . Therefore a major question f o r subsequent r e s o l u t i o n was, "As h y d r o p h i l i c i t y i s i n creased f u r t h e r , e i t h e r with charged or uncharged s u b s t i t u e n t s , w i l l potency continue to increase i n d e f i n i t e l y ( u n l i k e l y ) ? Or w i l l a s u b s t i t u e n t h y d r o p h i l i c i t y be encountered which i s optimal f o r potency i n the PCA r a t , f u r t h e r increases i n h y d r o p h i l i c i t y perhaps depressing potency?" E l e c t r o n i c e f f e c t s on potency are expressed by the second and t h i r d terms i n Equation B. Strongly e l e c t r o n - d o n a t i n g or with drawing e f f e c t s upon the 1 p o s i t i o n of the phenyl r i n g (the ( Σ σ ) term) continue to be q u i t e as d e l e t e r i o u s to potency as was i n d i cated by Equation A. However, the "F-5" term i n d i c a t e s t e n t a t i v e l y than an i n d u c t i v e l y electron-withdrawing s u b s t i t u e n t (high value of the Swain-Lupton F) i n the 5 p o s i t i o n may very sub s t a n t i a l l y enhance potency. A 5-substituent can e x i s t only when there are at l e a s t e q u i v a l e n t l y bulky s u b s t i t u e n t s at the 2 and/or 3 p o s i t i o n , so there are only two examples, the 3,5-CF3 (F-5=.38) and 3,5-NHCOMe (F-5=.28) d e r i v a t i v e s . However, both of these were much more a c t i v e than expected, 3,5-CF3 being the most s e r i o u s o u t l i e r f o r the s e r i e s as a whole. Further e x p l o r a t i o n of a l a r g e r range of v a r i a t i o n i n F-5 was c l e a r l y i n d i c a t e d . The next p a i r of terms i n Equation Β a t t r i b u t e s d e s i r a b i l i t y to c e r t a i n types of hydrogen-bonding groups attached to the meta and para p o s i t i o n s . The //345-HBD term implies that f o r every group of general type -HYR attached to the 3, 4, or 5 p o s i t i o n , where Y may be N, 0, or S and R may be anything i n c l u d i n g H or a 2


169


CRAMER ET A L .

9.

lone p a i r , potency i s enhanced by .42 l o g u n i t s . (At t h i s p o i n t , the r o s t e r of -YHR l i s t e d OH, SH, NH , NHCOR', and NHS0 R , where R = H, a l k y l , NH , or a r y l . ) Although t h i s trend i s r e a d i l y a t t r i b u t e d to a c t u a l hydrogen bonding between pyranenamine and i t s receptor, i t i s a b i t s u r p r i s i n g that any number of hydrogen bond donors i n any p o s i t i o n have equivalent and a d d i t i v e e f f e c t s . Since the trends i n $PI and //345-HBD portrayed by Equation Β would seem to p a r a l l e l one another, i t i s worth noting that the c o l i n e a r i t y between these v a r i a b l e s f o r a l l 98 compounds i s a c t u a l l y q u i t e small ( r = -.35). Thus these two trends i n Equation Β are c l e a r l y independent. The second hydrogen-bonding v a r i a b l e "NHS0 " i s s u b s t r u c t u r a l . Whatever the nature of the hydrogen-bonding i n t e r a c t i o n , the -NHS0 R group (which has the appropriate -YH-R substructure) apparently does not have s u i t a b l e p r o p e r t i e s . This p a i r of QSAR trends r a i s e s the question "What types and arrange ments of hydrogen-bonding groups w i l l and w i l l not enhance potency?" A range of p o s s i b i l i t i e s was explored i n the next roune of s y n t h e s i s . The M-V term implies a s i t u a t i o n which i s rather unusual i n medicinal chemical experience; increase i n the volume of meta (3or 5-) s u b s t i t u e n t s i s s t a t e d to increase potency. One might f u r t h e r ask, i n r e t r o s p e c t , whether i t i s reasonable to expect the s i z e s of these r e l a t i v e l y v a r i e d s u b s t i t u e n t types to occupy the same region of "receptor space" and to have commensurable e f f e c t s on potency, p a r t i c u l a r l y when the existence of a hydrogen-bonding term suggests a probable s p e c i f i c i t y of o r i e n t a t i o n f o r maximal receptor binding. P r e v i o u s l y published QSAR c o r r e l a t i o n s i n v o l v ing s i z e have been based mostly e i t h e r on small and n e a r l y symmetric groups or e l s e on h i g h l y f l e x i b l e groups such as higher a l k y l , not on l a r g e , angular, s e m i - r i g i d groups such as many of the groups i n t h i s s e r i e s must be. The v a l i d i t y of t h i s trend now seems dubious, but i n point of f a c t considerable QSAR e f f o r t was expended at t h i s s t a t e of s e r i e s development attempting to ascer t a i n an "optimal group s i z e . " F i n a l l y , the 4-0C0? term, the second most important to the o v e r a l l c o r r e l a t i o n , i s s u b s t r u c t u r a l and i n d i c a t e s that a c y l d e r i v a t i v e s of the 4-OH are f i v e times as potent as would be implied by the p h y s i c a l p r o p e r t i e s of the e s t e r s themselves. This trend i s c o n s i s t e n t with the view that these a c y l d e r i v a t i v e s be have as b i o l o g i c a l l y equivalent prodrugs, hydrolyzing i n v i v o to produce the 4-OH d e r i v a t i v e i t s e l f . f

2

2

1

2

2


2

"Second Generation" Pyranenamine (SK&F 78729). Insurmountable d e f i c i e n c i e s were encountered i n the secondary t e s t i n g of the 4-OH d e r i v a t i v e , and a new lead had to be chosen. Although not the most potent i n the primary screen, the 3-NH -4-OH d e r i v a t i v e (SK&F 78729) was found to possess the most d e s i r a b l e combination of p r o p e r t i e s i n secondary t e s t s . From the point of view of the "QSAR success s t o r y " , we note that the i n i t i a l QSAR study was c l e a r l y responsible f o r the type of s t r u c t u r a l m o d i f i c a t i o n which 2


DRUGS

170

AFFECTING

THE

RESPIRATORY

SYSTEM


q u i c k l y l e d to SK&F 78729. Indeed, i n the absence of the more potent pyranenamines r e s u l t i n g from QSAR, i t i s arguable that d i s appointment a r i s i n g from the d e f i c i e n c i e s of the 4-OH d e r i v a t i v e would have l e d to abandonment of the s e r i e s and even the research area i t s e l f . On the other hand, the p a r t i c u l a r v i r t u e s which d i s t i n g u i s h e d SK&F 78729 i n the secondary t e s t s have l i t t l e or nothing to do with the QSAR r e l a t i o n s h i p , which i s of course dependent on the primary t e s t (PCA r a t ) . F i n a l Phase of Pyranenamine Development. Most of the remain ing pyranenamines, l i s t e d i n Table I I I , were synthesized to answer s p e c i f i c QSAR or t r a d i t i o n a l SAR questions. As d e t a i l e d above, the key QSAR questions r a i s e d i n the intermediate s e r i e s develop ment concerned the p o s s i b i l i t y of a h y d r o p h i l i c i t y optimum, the need to i d e n t i f y potency-enhancing hydrogen-bonding groups, and the r e a l i t y of the F-5 and M-V terms. A considerable s y n t h e t i c e f f o r t went i n t o the p r e p a r a t i o n of p a r t i c u l a r e x o t i c s u b s t i t u e n t s , such as -NHC(=NH)NH , -CONH ( B a r b i t u r a t e ) , and -NHC0(CH0H) H, intended to help answer these questions. The r e g r e s s i o n equation which seems to best describe the QSAR f o r a l l 98 pyranenamines i s C. Compared with Equation B, a d d i t i o n a l terms r e l a t i n g to l i p o p h i l i c i t y , e l e c t r o n i c e f f e c t s , and hydrogen bonding have appeared, while the volume-related term has disappeared. 2

pl

r

2

5 0

- + + -

= .75

2

2

.59 - .33(+.ll) χ Σπ - .034(+.016) χ (Σπ ) 4.3(+1.6) χ F-5 + 1.3(+.85) χ R-5 - 1.7(+.62)x ( Σ σ ) .73(+.22) χ //345-HBD - .86(+.34) χ //HB-INTRA .69(+.28) χ //NHS02 + .72(+.35) χ 4-0C0? g = .48

F(9,88) =

2

28.7 2

The new l i p o p h i l i c i t y term, ( Σ π ) , when taken with the (Σπ) term c o n s t i t u t e s the f a m i l i a r d e f i n i t i o n of a p a r a b o l i c r e l a t i o n s h i p between potency and h y d r o p h i l i c i t y . The unusual aspect of t h i s p a r a b o l i c r e l a t i o n s h i p i s the remarkably h y d r o p h i l i c optimum, roughly -5, f o r the sum of s u b s t i t u e n t π v a l u e s . However, only one of the compounds has an estimated Σπ l e s s than -6 (3,5NHC0C00") and a l l of the π estimates f o r the half-dozen of these groups between -6 and -2.5, being based on group a d d i t i v i t y , must be regarded as probably too h y d r o p h i l i c . I t i s a l s o p o s s i b l e that negative charge, rather than extreme h y d r o p h i l i c i t y , i s the pro p e r t y d e l e t e r i o u s to potency (although the n e c e s s a r i l y concomitant hypothesis, that potency increases p a r a l l e l h y d r o p h i l i c i t y without l i m i t , seems d i f f i c u l t to a c c e p t ) . Therefore t h i s r e l a t i o n s h i p between potency and h y d r o p h i l i c i t y must be regarded as q u a l i t a t i v e l y c o r r e c t only. The e l e c t r o n i c aspects of Equation C represent an extension of those discussed f o r Equation B. The ( Σ σ ) term continues to i n d i c a t e the d e s i r a b i l i t y of an o v e r a l l σ near 0, while the F-5 2



9.

CRAMER ET AL.

ÇSAR


171

term now s t r o n g l y a s s e r t s the value of nevertheless a t t a c h i n g i n d u c t i v e l y withdrawing s u b s t i t u e n t s to the 5 p o s i t i o n . The R - 5 term b u t t r e s s e s the F - 5 term by i t s i n d i c a t i o n that resonance withdrawing e f f e c t s as w e l l as i n d u c t i v e l y withdrawing e f f e c t s of a 5 s u b s t i t u e n t w i l l promote potency. Hydrogen bonding, or some other c h a r a c t e r i s t i c of the -YHR group as defined above, has become the most important i n f l u e n c e on r e l a t i v e potencies (_i.£., the 345-HBD term has the l a r g e s t F - t e s t ) , provided that the c o n s t r a i n t s on hydrogen-bonding implied by the two terms //HB-INTRA and //NHS02 are accepted. The //345-HBD term i n d i c a t e s that potency i s enhanced f o u r f o l d f o r each -YHR substituent. However, the //HB-INTRA term i n combination with the //345-HBD term i n d i c a t e s that a -YHR which i s capable of forming an i n t r a m o l e c u l a r hydrogen-bond ( f i v e or six-membered r i n g ) with an ortho s u b s t i t u e n t w i l l not enhance potency. As i n Equation B, the e f f e c t of the NHS02 term i s to exclude - N H S O 2 R groups from t h i s potency-enhancing -YHR c l a s s of s u b s t i t u e n t s . The remaining term, 4 - 0 C 0 ? , continues to a s c r i b e s p e c i a l potency enhancement to a c y l d e r i v a t i v e s of the 4-OH pyranenamine, p o s s i b l y by way of the pro-drug mechanism. However, the M-V e f f e c t w i t h i n Equation Β has not p e r s i s t e d s t r o n g l y . Although a s l i g h t l y favorable i n f l u e n c e of s u b s t i t u e n t volume, p a r t i c u l a r l y of meta s u b s t i t u e n t s , would be the next term to enter Equation C, the a s s o c i a t e d increase i n r and decrease i n s would be only . 0 1 units. The o v e r a l l s t a t i s t i c a l q u a l i t i e s of Equations C, B, and A are much more a l i k e than would be supposed from comparison of r values alone. The variance not explained by the r e s p e c t i v e equations has remained s t a b l e as the range of potency spanded by the pyranenamine s e r i e s expanded, the s values of .48, .40 and .48 being somewhat l e s s than the estimated experimental v a r i a b i l i t y and t h e r e f o r e u n l i k e l y to be improved upon i n a meaningful way by adding more terms to the equations. The improvement i n r from .48 to . 7 7 i s the r e s u l t of the increased spread i n potency, i n t u r n brought about by the success of the o r i g i n a l QSAR i t s e l f ! The pyranenamine found to be the most potent of a l l , the 3,5-NHCO(CHOH)2H d e r i v a t i v e , e x e m p l i f i e s the t r a i t s that Equation C i n d i c a t e s as d e s i r a b l e : The two h i g h l y p o l a r - N H C 0 ( C H 0 H ) 2 H groups give an estimated s u b s t i t u e n t t o t a l π value of - 6 . 2 , not f a r from the presumed optimum π. There are two -YHR groups, which being meta are assumed not to form an i n t r a m o l e c u l a r hydrogen bond. The 5 - (or 3 - ) s u b s t i t u e n t has a p o s i t i v e F value of +.28, some what o f f s e t by a negative R value of -.25, producing an o v e r a l l n e g l i g i b l y p o s i t i v e σ of . 3 7 or Σ σ of .14. When i n s e r t e d i n t o Equation C, t h i s combination of p r o p e r t i e s y i e l d s a p r e d i c t e d P I 5 0 of 2 . 3 . The a c t u a l P I 5 0 of + 3 . 0 corresponds to an I D 5 0 of 1 0 ~ 3 mg/kg, or e f f e c t i v e b i o l o g i c a l a c t i v i t y at nano-molar admin i s t e r e d blood l e v e l s . 2

2

2

2


DRUGS A F F E C T I N G T H E RESPIRATORY S Y S T E M

172

Table I I I ;

Compounds Synthesized i n Order to E s t a b l i s h a F i n a l QSAR, and Miscellaneous.

Substituent

pl50

Rationale

4-Br

- .7

3

2- C00Et

- .5

3

3- OCH COOH

- .7

3

3-NHMe

- .7

2

+ .1

1

3-NHC=NHNHS0 Ph(p)Me

- .7

3

3-NHCOCH CH COOEt

+ .3

2

3- NHS0 NH

+ .5

1

+ .5

1

3-NHC00Et

+ .4

2

3-NHC0C00""

+1·5

2

3-NHCO(CHOH) H

+1.3

1

3-CH NHCOCH

- .7

3

3-CONH

- .7

2

3-CONHMe

+ .2

2

- .7

2

+ .2

1

- .5

2


2

3-NHC=NHNH

2

2

2

2

2

2

4- NHS0 NH 2

2

2

2

3

2

3-C0N(Me) 0

y 9

3-C0NH- ^

a

NH

^ 0

0 3-0H-4-NH

2

a

Codes the r a t i o n a l e f o r s y n t h e s i s : 1 = QSAR; 3 = c l a s s i c a l m e d i c i n a l chemistry; 2 = both. See D i s c u s s i o n .


9.

CRAMER ET AL.

ÇSAR Development of Pyranenamines

Table I I I (Continued)

Substituent

P*50

Rationale

3-NHMe-4-OH

- .7

2

3-CH NHMe-4-OH

- .7

2

3-CONHMe-4-OH

+ .1

2

3-NHS0 Me-4-OH

- .8

2

3-OH-5-NH

+ .2

2

3-NHCOMe-5-OH

+1.7

1

3-NHCOMe-5-NH

+1.0

2

3,5-NH

+ .3

2

3,5-NHCOEt

+2.5

2

3,5-NHCO(n)Pr

+1.3

2

3,5-NHCOOEt

+ .6

2

3,5-NHCOCOOEt

+1.7

2

3,5-NHCOCOO"

+1.5

2

3,5-NHCO(CHOH) H

+3.0

1

3,5-NHS0 Me

+ .5

2

3,5-NHS0 Ph

- .7

2

3,4,5-OH

+ .4

2

- .5

2

2


2

2

2

2

2

2

2

3-OH-6-NH

2

a

3

Codes the r a t i o n a l e f o r s y n t h e s i s : 1 = QSAR; 3 = c l a s s i c a l m e d i c i n a l chemistry; 2 = both. See D i s c u s s i o n .



174

DRUGS A F F E C T I N G T H E

RESPIRATORY

SYSTEM

Drug/Receptor Binding* I t i s fashionable to derive a specu l a t i v e p h y s i c a l model of drug/receptor binding from the physicochemical i n f l u e n c e s upon potency which are suggested by a QSAR. C e r t a i n l y an unusual feature of the present QSAR i s the tendency f o r potency to increase, rather than decrease, with i n c r e a s i n g h y d r o p h i l i c i t y (or decreasing l i p o p h i l i c i t y ) . The assumption that t h i s h y d r o p h i l i c i t y dependence i s r e l a t e d to receptor binding, rather than t r a n s p o r t , i s s t r o n g l y supported by the a d d i t i o n a l potency introduced by s p e c i f i c -YHR groups, hydrogen-bonding of course being a property that tends to p a r a l l e l h y d r o p h i l i c i t y . The s p e c i a l e l e c t r o n i c i n f l u e n c e of 5 s u b s t i t u e n t s , e l e c t r o n withdrawing character p a r t i c u l a r l y v i a an i n d u c t i v e mechanism being d e s i r a b l e , i s easy to r a t i o n a l i z e as being caused by an e l e c t r o s t a t i c a t t r a c t i o n to some adjacent e l e c t r o p o s i t i v e receptor moiety, perhaps NH3+R. However, t h i s r a t i o n a l i z a t i o n r a i s e s a s u b s i d i a r y question which i s not u s u a l l y given a t t e n t i o n i n QSAR s t u d i e s . Whenever the aromatic r i n g i s unsymmetrically s u b s t i tuted, i t cannot automatically be assumed that a l l 3 or a l l 5 sub s t i t u e n t s i n t e r a c t with the receptor i n the same way. The aro matic r i n g has the p o s s i b i l i t y of f l i p p i n g , such that some 3 sub s t i t u e n t s may behave as 5 s u b s t i t u e n t s and some 5 substituents as 3's, depending on the r e l a t i v e p h y s i c a l p r o p e r t i e s of the 3 and 5 s u b s t i t u e n t s and the p h y s i c a l p r o p e r t i e s which dominate i n t e r a c t i o n between the receptor and the aromatic r i n g . In t h i s t r e a t mean of the pyranenamine s e r i e s , unsymmetrical s u b s t i t u t i o n pat terns have been e x p l i c i t l y assumed to o r i e n t themselves on the b a s i s of s i z e , the more bulky group(s) being p o s i t i o n e d 2 and/or 3. This i s the usual i f perhaps unconscious b a s i s f o r a s s i g n i n g p o s i t i o n s i n QSAR work, because any unnamed s u b s t i t u e n t on an aromatic r i n g i s H-, the smallest of a l l s u b s t i t u e n t s . However, the e l e c t r o s t a t i c i n t e r a c t i o n which appears to e x i s t between a 5-substituent and the receptor appears to be a second p o s s i b l e o r i e n t i n g i n f l u e n c e , capable of competing with a s t e r i c i n f l u e n c e . It i s not obvious, f o r example, why a 3-C1 s u b s t i t u e n t , a small group with a s t r o n g l y p o s i t i v e F value, could not be a t t r a c t e d to the e l e c t r o p o s i t i v e moiety apparently adjacent to the 5 - p o s i t i o n , thereby being much more s t r o n g l y bound and potent than might otherwise be expected. The p o s s i b l e p h y s i c a l s i g n i f i c a n c e of the other e l e c t r o n i c term, $SIG**, a l s o merits some d i s c u s s i o n . The general p r a c t i c e i n QSAR work i s to f o l l o w the precepts of p h y s i c a l organic chem i s t r y and to use only the Hammett σ as an o v e r a l l measure of e l e c t r o n i c e f f e c t s . However, i t should be recognized that the Hammett σ i s experimentally defined s t r i c t l y as a measure of a p a r t i c u l a r c l a s s of intramolecular e l e c t r o n i c e f f e c t s . . . t h e pre dominantly through-ring e f f e c t of s u b s t i t u e n t s ortho, meta, and/or para upon a center undergoing some s o r t of covalent change. In c o n t r a s t , drug/receptor binding u s u a l l y does not involve covalent bonding changes at a l l . When e l e c t r o s t a t i c a t t r a c t i o n s are im portant, as postulated above f o r the 5 - p o s i t i o n w i t h i n the


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pyranenamine s e r i e s , the e f f e c t of e l e c t r o n i c changes elsewhere i n the r i n g on t h i s i n t e r a c t i o n would seem to be b e t t e r expressed by summing the weighted F- and R-values of the s u b s t i t u e n t s ortho, meta, and para with respect to the i n t e r a c t i n g p o s i t i o n , not with respect to the 1 p o s i t i o n . In the pyranenamine s e r i e s , the f i n d i n g that the Hammett σ (squared) i t s e l f ( Σ σ ) i s a u s e f u l c o r r e l a t e seems most reasonably a t t r i b u t a b l e to an e l e c t r o n i c e f f e c t s p e c i f i c a l l y at the 1 p o s i t i o n of the aromatic r i n g . A p o s s i b l e p h y s i c a l i n t e r p r e t a t i o n i s that the e l e c t r o n i c character of the r i n g i n f l u e n c e s e l e c t r o n d i s t r i b u t i o n w i t h i n the enamine moiety i n a manner s i g n i f i c a n t f o r receptor binding or a c t i o n , with the i d e a l e l e c t r o n i c d i s t r i b u t i o n being that produced by the unsubstituted phenyl r i n g . Downloaded by UNIV ILLINOIS URBANA on May 2, 2013 | http://pubs.acs.org Publication Date: February 22, 1980 | doi: 10.1021/bk-1980-0118.ch009

2

Discussion: The c o n t r i b u t i o n s of QSAR to the development of the pyranenamines were s u b s t a n t i a l at a l l stages of the program. As discussed above, an immediate potency enhancement of almost an order of magnitude was produced by the f i r s t g r a p h i c a l QSAR, s p e c i f i c a l l y by the 3-NHAc-4-0H pyranenamine, whose de-N-acylated d e r i v a t i v e became the c l i n i c a l lead SK&F 78729. Continued p u r s u i t of these and other trends u l t i m a t e l y l e d to the 3,5-NHCO(CHOH)2H pyranenamine, a thousand times more a c t i v e i n the PCA r a t assay than any member of the o r i g i n a l s e r i e s . These successes were by no means i s o l a t e d . Throughout the development of the s e r i e s , i n t u i t i o n continued to play an impor tant r o l e i n the s e l e c t i o n of s y n t h e t i c t a r g e t s , and therefore i t i s p o s s i b l e to make a rough o v e r a l l comparison of the performances of the QSAR equations with the performance of i n t u i t i o n . Of course, these two " r a t i o n a l e f o r s y n t h e s i s " would not n e c e s s a r i l y c o n f l i c t and almost h a l f of the s e r i e s seemed reasonable s y n t h e t i c targets from e i t h e r point of view. However, there were compounds which, because of e i t h e r s y n t h e t i c d i f f i c u l t y or simple o b s c u r i t y , would not have been prepared without a s p e c i f i c QSAR-based recommendation, and there were other compounds which were synthe s i z e d despite unfavorable QSAR auguries. F i n a l l y , the compounds i n Table IA of course predated any p o s s i b l e QSAR r a t i o n a l e . These c o n s i d e r a t i o n s allow the 98 pyranenamines to be d i v i d e d i n t o four c l a s s e s , based on " r a t i o n a l e f o r s y n t h e s i s " and the mean e x p e r i mental potencies w i t h i n each c l a s s to be computed:

# of Examples

Class Class Class Class

1 2 3 4

1

0

QSAR""; t r a d i t i o n a l QSAR+; t r a d i t i o n a l * QSAR"; traditional"** QSAR unavailable

13 47 19 19 98

Mean P 50 C+s.d.) I

+ .68 (+.86) + .20 (+.80) - .29 (+.41) -1.09 (+.91) - .08 (+.91)


DRUGS A F F E C T I N G T H E


176

RESPIRATORY

SYSTEM

The c l a s s of " s y n t h e t i c r a t i o n a l e " which seemed to be most r e s p o n s i b l e f o r the synthesis of a p a r t i c u l a r pyranenamine can be seen i n the l a s t column of Tables I, I I , and I I I . The key comparison of mean PI50» i n s o f a r as the r e l a t i v e per formance of QSAR and medicinal chemistry r a t i o n a l e i s concerned, i s Class 1 ^ s . Class 3. C l e a r l y the average PI50 of compounds chosen s o l e l y on a QSAR basis (Class 1) i s almost an order of magnitude higher than the average PI50 of those synthesized despite QSAr considerations (Class 3). If one makes the usual s t a t i s t i c a l assumption about the normality of d i s t r i b u t i o n of the i n d i v i d u a l compound potencies w i t h i n Classes 1 and 3, the prob a b i l i t y of encountering such a d i f f e r e n c e i n mean p ^ o ' s i f QSAR i n f a c t has no relevance to p r e d i c t i n g compound potency i s l e s s than .005, according to a T - t e s t . One might a l s o ask whether, given that i n general the s o l e l y QSAR-based compounds (Class 1) were harder to make than those d e s i r a b l e from both t r a d i t i o n a l and QSAR c o n s i d e r a t i o n s (Class 2), the extra e f f o r t produced compounds of s i g n i f i c a n t l y greater potency. T h i s i n t r a - c l a s s d i f f e r e n c e i s a l s o s i g n i f i c a n t , but only at the .05 l e v e l . The f i n a l comparison p o s s i b l e , between Classes 2 and 3, might be taken as a measure of to what extent, ignoring the more e x o t i c s u b s t i t u e n t s of Class 1, the QSAR was a u s e f u l supplement to t r a d i t i o n a l considerations alone i n p i c k i n g targets once the fundamental d e s i r a b i l i t y of i n creased h y d r o p h i l i c i t y was recognized. This l a s t d i f f e r e n c e i n means i s s i g n i f i c a n t at the .01 l e v e l . Encouraging as the preceding argument i s to QSAR advocates, i t s improvement i s s t i l l p o s s i b l e . A weakness i n the argument i s that membership i n the four i n d i v i d u a l c l a s s e s may a l s o be biased with respect to t h e i r time of discovery. Since the average l e v e l of potency among pyranenamines g e n e r a l l y increased with greater knowledge, might not the c l e a r c u t tendency f o r potency to increase with decreasing " c l a s s number" simply r e f l e c t a tendency f o r potency to increase with i n c r e a s i n g experience? As a rough numer i c a l i n d i c a t o r of experience, the SK&F// (accession number) can be used; i t s bias i s anti-QSAR s i n c e Class 1 compounds u s u a l l y took longer to make once t h e i r synthesis had been decided upon, and thus received a higher SK&F//, than d i d Class 2 or Class 3 com pounds. Class 4 compounds, those on which the i n i t i a l QSAR was based are i r r e l e v a n t to t h i s question and are not considered. The c o l i n e a r i t y of SK&F// and " r a t i o n a l e c l a s s " i s i n f a c t low, r=.4 when Class 4 compounds are excluded. Regression of PI50 against SK&F// and " r a t i o n a l e c l a s s " together y i e l d s the f o l l o w i n g equation: pl

5

= - 2.79 + 4.8(+5.9)xl0~ χ SK&F// - .40(+.28) χ " r a t i o n a l e c l a s s //"

5 0

r

2

= .18

s = .72

F(2,76) =

8.6


9.

CRAMER ET AL.


177

2


Although the r value i s minuscule by QSAR standards, the c o r r e l a t i o n i s s i g n i f i c a n t at the .0005 l e v e l according to the Ft e s t . From the r a t i o of 95% confidence i n t e r v a l to c o e f f i c i e n t s i z e i n the two forms, i t i s evident that " r a t i o n a l e c l a s s " i s a much more important i n d i c a t o r of potency than i s SK&F#, and so the p o s s i b i l i t y that the apparent dependency of potency upon " r a t i o n ale c l a s s " i s a c t u a l l y an a r t i f a c t of i n c r e a s i n g experience can be excluded. Conclusion: This QSAR success s t o r y comprises a very s a t i s f a c t o r y r e b u t t a l to the c r i t i c i s m s of previous QSAR " p r e d i c t i o n s " l i s t e d i n the I n t r o d u c t i o n . S p e c i f i c a l l y : 1) The extent of the potency enhancement, from an o r i g i n a l potency range spanning perhaps two orders of magnitude immediately to three orders and u l t i m a t e l y to f i v e orders of magnitude, i s hardly t r i v i a l . 2) As j u s t discussed, the enhancements i n potency produced by the use of QSAR are e n t i r e l y too c o n s i s t e n t , across the s e r i e s and over time, to be a t t r i b u t e d to chance. 3) A non-regression but physicochemically based s t r a t e g y for developing an optimal compound, the T o p l i s s t r e e , had not succeeded a t a l l i n i d e n t i f y i n g the "most potent compound". In order to b e t t e r understand t h i s f a i l u r e to detect what, a f t e r a l l , was a π/σ r e l a t i o n ship of a type where the T o p l i s s t r e e should have been productive, i t i s suggested that the i n t e r e s t e d reader connect the T o p l i s s d e c i s i o n points i n a "Craig p l o t " such as Figure I. I t w i l l be apparent that c r i t i c a l d e c i s i o n s about π or σ dependency w i l l be made o f t e n as the r e s u l t of two experimental points only. Nevertheless, the T o p l i s s tree s t i l l appears to be, as i t s adherents c l a i m , an e x c e l l e n t and r a t i o n a l b a s i s for g i v i n g oneself a good chance to i d e n t i f y more a c t i v e compounds at an e a r l y stage, before QSAR studies are p o s s i b l e . Furthermore, even an unsuccessful study such as t h i s one d i d y i e l d a s a t i s f a c t o r y d i s t r i b u t i o n o f compounds f o r subsequent QSAR work. 4)

Although many members of t h i s s e r i e s might, sooner or l a t e r , have been prepared without the i n f l u e n c e of QSAR studies ( i f the p r o j e c t had s u r v i v e d the d i s a p p o i n t i n g secondary t e s t s of the 4-OH d e r i v a t i v e ) , the compounds i n Class 1 f o r the most part represent very unusual sub s t i t u e n t s which are almost never encountered i n medici nal chemistry research programs.


178

DRUGS AFFECTING THE RESPIRATORY SYSTEM

References and Footnotes


1.

Reviewed in C. Hansch, M. Yoshimoto, and M. H. Doll, J. Med. Chem. 19, 1089 (1976), R. D. Cramer III in "Annual Reports in Medicinal Chemistry", Vol. 11, F. H. Clarke, Ed., Academic Press, 1976, p. 301, and J. G. Topliss and J. Y. Fukunaga, "Annual Reports in Medicinal Chemistry", 1978, Chapter 30, in press. Recent tests of predictions include C. Grieco, C. Silipo, A. Vittoria, and C. Hansch, J. Med.Chem.20, 596 (1977); C. Hansch and J. Y. Fukunaga, ChemTech 7, 120 (1977); and J. T. Harrison, W. Kutch, J. J. Massey, and S. H. Unger, J. Med.Chem.21, 588 (1978).

2. K. R. H. Wooldridge, Proc. 5th Int. Symp. Med.Chem.,Paris, July 19-22, 1976, J. Matthieu (Ed.), p. 427. I thank J. G. Topliss for referring me to this work. 3.

J. G. Topliss, J. Med.Chem.15, 1006 (1972); Y. C. Martin and W. J. Dunn III, J. Med.Chem.16, 578 (1973), J. G. Topliss and Y. C. Martin in "Drug Design", Vol. 5, E. J. Ariens, Ed., Academic Press, 1975, p. 1.

4. K. M. Snader, L. W. Chakrin, R. D. Cramer III, Y. M. Gelernt, C. K. Miao, D. H. Shah, J. W. Venslavsky, C. R. Willis, and Β. M. Sutton, preceding paper. 5. R. D. Cramer III, Κ. M. Snader, C. R. Willis, L. W. Chakrin, J. Thomas, and Β. M. Sutton, J. MedChem.,in press. 6. T. M. Bustard, J. Med.Chem.17, 777 (1974); N. J. Santora and K. Auyang, J. Med.Chem.18,959 (1975); F. Darvas, J. Med.Chem.17, 799 (1974). RECEIVED

August 14, 1979.


The Development of Antiallergic Pyranenamine Series: A QSAR

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