Journal of Scientific & Industrial Research

Vol. 62, June 2003 , pp 537-553

Selective Phosphodiesterase 4 Inhibitors - Emerging Trends in Astluna Therapy (Antiasthmatics-3)

Ranju Gupt a*, Oeepika Gandhi and Oharam Paul Jindal

University Institute of Pharmaceuti cal Sciences, Panjab Universit y, Chandigarh 160014

Considerable interest has been generated in the potenti al utility of isozyme selective inhibitors of phosphod iesterases in the treatment of asthma and other inflali1matory disorders. Heterogeneity in ti ssue distribution as well as their different fun cti onal roles make these enzymes very attract ive targets for medicinal chemists . To date at least II different fami lies of POE isozymes are known , among which POE 4 plays a major role in mod ul ating the activity of virtually all cell s involved in the inflammatory process. In hibitors of thi s enzyme family display impressive antiasthmatic ac ti vity by red ucing the bronchial smooth mu scle tone and considerable anti-inflammatory activity. The review detail s the various classes of POE 4 inhibitors stru cturall y related to rolipram, nitraquazone and xanthines, which appear to be very attractive models for synthesis of novel selecti ve POE 4 inhibitors potentially useful for the treatment of asthma and chronic obstructive pulmonary di seases. Rationale for the use of POE4 inhibitors in the treatment of asthma is also discussed.

Key words: Phosphodiesterase 4 inhibitors , Asthma therapy, Antiasthmatics , Isozyme, Rol ipram, Nitraquazonc. Xanthincs.

Introduction

There has been growing interest in recent years

tn the utility of selective phosphodiesterase (POE)

inhibitors as novel targets for drug d iscovery.

Phosphod ies terases comp ri se a heterogenous group

of isozy mes which differ neverthe less in their

kinetic and phys ical characterist ics, substrate

(cAMP or cGMP) se lect ivities, sens itivity to

e nd ogenous activators , susceptibility and response

to phosphorylation by protein kinase, tissue distribution and subce llular loca li zation l

-, . These

isozy mes hydrolyse the 3'-phosphodiester bond of

cyclic messengers cAMP or cGMP to their inactive

S'-nuc leo tide forms. cAMP and cGMP are

ubiquitous intracellular second messengers which

playa prom ine nt role in the regulation of important

cellular fu nct io ns such as secretion, contraction,

metaboli sm and growth. T he e levation of their

intrace llular levels by POE inhibitors represents a

useful st rategy for eliciting a variety of

pharmacologica l effects.

* Author for correspondence ranju29in @yahoo .co.in

Phosphodiesterase Superfamily

At least e leven diffe rent fami lies of POE isozymes are known based on the ir substrate spec ificity (cAMP or cGMP) kinetics, and the ir responsi veness to a ll osterics modulator and e ndogenous or exogenou s regulators 1-9 (Tab le I).

Each POE fam il y inc ludes subfamilies that are e ncoded by distinct genes but have 70-80 per cent homology with one another and finally contain several members. The fami I ies of POEs are re ferred by Arab ic nume ral s (1-10), subfamili es by capita l le tters (A-D) and members by Arabic numeral s (1-3). Nearly a ll these different POEs have unique primary sequence in the ir cata lytic or regulato ry domains and they are often se lectively expressed. This implies that it may be possible to modulate individual isozymes using specific drugs. The differing distributi on of POEs between ce ll types, the large divers ity in structure, funct ion and regu lation among POE isozy mes makes it possible to develop selective and poss ibl y the rapeutically useful inhibitors and act ivators of individual isozymes, which will be devoid of unnecessary side effects. A number of inhibitors of phosphodiesterase isozymes have been described). They can be used as cardiotonics,

538 J SCI IND RES VOL 62 JU E 2003

Tab i<.: 1- Charactcri sti cs of phosphodiesterase isozyme families.

Family Isozyme Binding Specific Loca li zation (subfalllil y) specificity inhibitors

I(A.B.C) Calciulll/ cA MP or Vinpocetine. Nerve ti ssue. ca lmodulin cGMP phenothiazine mast cells. stilllulated tracheal

epithelium. T cells

2A( I-:l) cGMP Low affinit y Erythro[hydrox Platelets, stilllulated fo r cA MP yl-nonyl] - endothelium,

and cGMP adenine Illacrophagcs

:l(A.B) cGMP Hi gh Siguazodan, SlIlooth lIluscle, inhibited affinit y for cilostazo l. T cel ls. basophils.

cAMP lIlilrinone. macrophagcs. cilostamide epithelial cells.

adipocytes

4(A.B.C D) cAMP High RO-20- 1724. Inflammatory spec ifi c affinit y for ro li pralll. cells. neuronal

cAMP CDP-8.J O. ti ss ue SB -207499, RP-7J40 1

SeA) cGMP High Zaprinast. Platelets. lung specific aflinity for S K&F-962:l 1; epithelia l cells

cGMP dipyridilllolc

6(A.B.C D) Photo- High for Dipyridilllole. Retina l rods and receptor cGMP, Iow zaprinast cones

for cAMP

7(A. B,CD) Rolipmm High None T cells, B cell s. insensiti ve aflinity for skeletal muscle.

cAMP hean

ant i thrombotic agents, vascular and airway smooth muscle re laxants, anti-i nfl ammatory agents and antidepressants. The knowledge that - (a) multiple dist inct POE isozymes ex ist , (b) Isozymes differ in their cellular di stribution ancl synthesis of a variety of inhibitors possessing marked degree of selectivity for one isozyme over other, raises the poss ibility that the unfavourable side effects profile of nonselecti ve POE in hibitors can be reduced by synthes izing compounds that are targeted specifical ly for the isozymes that predominates in the particular tissue or the cell of . to Interest .

Recently, selective phosphodiesterase inhibitors have received considerable attention ' as molecular targets fo r the development of antiasthmat ic agents. Several comprehensive reviews have been published recently on the use of POE 4 inhibitors in the treatment of asthma3.7.8. 11 .12.

Phosphodiesterase Inhibitors in Asthma

Bronchial asthma is a noninfecti ous respiratory pathology invo lving the concerted actions of multiple in flammatory cell s, spasmogens, infl ammatory

mediators, cytoki nes and growth factors. Acute airway obstlUction, bronchial hyperresponsiveness ancl inflammatory state of bronchial mucosa with increased level of inflammatory mediators characteri se this pathology. Eos inophil s also playa prominent role in asthma sugge ting it to be an inflammatory disorder8.11 . Today asthma is affecting over 5 per cent of the adu lt populat ion and perhaps upto 10 per cent of children. It is rising in prevalence, severity and mortalit y in the devel oping countries despite substan tial increase in number of newer antiasthmatic agentsH

. Many c lasses of dru gs like leu kotriene receptor antagon ists, 5-1 i pox ygenase inhibitors, adenos ine antagoni sts. 'l11ticholinergics , ~ 2-agoni s t s, glucocortico ids and an tihi stamines are al so used as effecti ve bronchodiiators·15

.II

.

~ 2Adrenocepto r agon ists are widely used in asthma therapy and on inhalation prod uce in stant bronchodilation. They however have littl e effect on underl ying inflammation and becau - of thi s reason their regular and long term use has been debated 8. 12-15 . Systemic side effects such as tachycard ia, pa lpitation and headache are observed with inhaled B­adrenoceptor agoni sts and also the self-admin istration of inhaled drugs may be difficult for o ld and disabl ed persons. Glucocort ico ids on the other hand have well documented anti-inflammatory properties and can reduce ai rway hyperrespons iveness but lack immediate bronchodilatory action l 2

. Chron ic admini stration of glucocort icoids can cause significant suppress ion of hypotha lamus pituitary adrenal (HPA) ax is and of bone growth in children. It may also affect di sease progression. Two detai led reviews have been publi shed by l indal ei al.16

.17 on

Bradrenoceptor agoni sts and methylxanthines as antiasthmatics .

Novel ora ll y acti ve anti asthmat ic drugs whi ch di sp lay both bronchod ilatory and an ti -infl ammatory profile with reduced side effects and also wh ich can substitute the combined therapy of inhaled B2-receptor agonists (bronchodi lators) and cort icosteroids (anti-inflammatory) is the need of hour. One class of drugs, whi ch we can look forward for effective as thma therapy with bot h bronchodil atory and glucocorticoid like anti-infl ammatory property can be selecti ve phosphodiesterase inhibitors . Phosphodiesterase (POE) inhibitors result in en hanced intracellu lar leve ls of second messengers cAMP and cGMpx.12, which are generall y associated with dampening

GUPTA e/ al.: SELECTIVE PHOSPHODIESTERASE 4 I HIBITORS 539

effects on airway smooth muscle. cAMP suppresses the ac ti vation and mediator release from infl ammatory cell s' 2.'8.,'J (Figure I ). These mediate the fun cti onal responses of ce ll s to a mu ltitude of hormones, neurot ransmitters and autoco ids with respect to the regul atory functi on of cells in vo lved in path ophysiology of asthma. So POE inhibitors have a theoreti cal advantage over the use of other anti as thmati c agents that in hi bit the formation or antagoni ze the act ion of indi vidual mediators.

Phosphodiesterases 3, 4 and 5 are particularly important with respect to targets for the development of novel anti asthmati c agents. 5

.20 The mi xed anti­

infl ammatory and bronchodil atory profil e of POE inhibitors could all ow the di scovery of new agents able to compete and rep lace cOlt icosteroids and ~2 agoni sts, which so fa r represent the basis of therapeutic management of asthma8

. All five (1-5) major types of isozymes are found in human airways. The ro le of POE I and POE 2 isozymes have not been clarified due to lack of potent and selecti ve inh ibitors of these two isozymes). Much of the emphasis on selec ti ve POE inhibitors for as thma therapy has been focused on POE 4, which is a cAMP specific isozyme with a Kill of 3 jJ.M for cAMP and more than 3,000 11M fo r cGMP21. There are atleast two main reasons fo r the bas is of growing interest in the chemical, pharmaco logical and biochemica l research in the area

Cyclic AMP

Adenylyl Cyclase

! ATP ~ cAMP ~ S'-AMP

! cA-PK cA-PK

(inactive) ~ (active)

}/"~

of selec ti ve phosphodiesterase 4 inhibitors. First, there is general conviction that the dual anti­infl ammatory and bronchodi latory profile of POE 4 inhibitors could lead to the discovery of new agents able to compete and perhaps to replace corticosteroids (ant i-inflammatory) and ~2 agoni sts (bronochodil ators), the bas ic therapeut ic agents for the management of as thma and second, new and promlsll1g therapeutic app l ications of POE 4 inhibitors in certain autoimmune di seases, e.g., rheumatoid arthriti s, mu lt iple sc leros is and type 2 di abetes8.22. .

Selective PDE 4 Inhibitors as Antiasthmatic Agents

Inhibitors of low Kill, cAMP-spec ific type 4 isozymes in particular are attracti ve targets as potenti al anti asthmatic agents. This isozyme exerts a key role in regulati on of infl ammatory cell s implicated in the pathology of the di sease410 because of its tissue di stribution. POE 4 is also an important enzyme in human bronchi23

. They inhibit superoxide generation in monocytes, macrophages, neut roph il s and eos inophi ls, reduction of TNFa release in monocytes and macrophages and su ppress ion of chemotax is and phagocytosis '5,2.J. Inhibition of medi ator synthesis or release from mast cells, basophils, eos inophil s, neutrophi ls, macrophages and

Cyclic GMP

Guanylate Cyclase

! S'-GMP +--- cGMP +--- GTP

cG-PK (active)

}/"

! cG-PK

+--- (inactive)

r---------------------------~ ~----------------------------~ t INFLAMMATORY CELL ACTIVITY I I t AIRWAY SMOOTH MUSCLE TONE I

Figure 1- Ro le o r cycl ic nucleotides in the function o f infl ammatory cell s and airway smooth muscle

540 J SC I INO RES VOL 62 JUNE 2003

T- Iymphocytes have also been demonstrated. PDE 4 inhi bitors have the ability to reduce the bronoc hospasm induced by hi stamine, leukotri ene D~(L TD4), ca rbachol and methacholine8

.25 Se lective

in hib itors of PDE 4 may address not onl y asthmatic bronc hoconslricti on but also underl ying bronchi al infl ammati on.26 Thus the pro fil e of se lec ti ve PDE 4 inhi bitors seems to fulfill the requirements for a unique therapy fo r asthma.

From a structu ra l po int of view, selec ti ve PDE 4 inh ib ito rs can be divided into 4 classes.

Catec hol ethers : Struc tural analogues of rolipram (1).

2 Heterocycl ics and analogues: Structural analogues of nitraquazone (2).

1 Xanthines and re lated co mpounds Structural analogues of theophylline (3).

4 Miscell aneous Selecti ve PDE 4 Inhibitors

o

(1 )

(3)

Co/echol Ethers

Rolipram (1) is the prototype of thi s class of selective PDE 4 inhibitors. Rolipram originally developed, as an antidepressant is now the most studied of all selecti ve PDE 4 inhibitors. SAR studies of a series of rolipram analogues as PDE inhibitors have been published). Rolipram has been found to bind to a high affinity site on POE 4, distinct from catalytic site27 . While hi gh affin ity rolipram binding site do not appear to be present in all ti ssues that contain PDE 4,

thi s acti vity is coexpressed with hu man recombi nant PDE 4 ac ti vity. The bronchodilatory effec t of several PDE 4 inhibitors correlate better with di sp lacement oj ro lipram binding than with POE 4 inhi bition18

.2Y . In

addit ion to hav ing desirable in hibitory effects on inflammatory, anaphylax is and smooth muscle contracti on, selecti ve POE 4 inhibitors also produce undes irable side effects including nausea and vomiting. POE 4 inhibitors also potenti all y disp lace e H] roli pram from a high affinity binding site which is proposed to be an allosteric binding site on POE 4 enzy me. Emetic potency of PDE 4 inhibitors is corre lated with affinity fo r rolipram binding site in brain rather than potency of inhibiting PDE 4 enzyme acti vity . Also the most obvious concern regarding the POE 4 inhibitors stems from their antidepressant activ ity re 'ulting from their inhibition of PDE 4 in the brain . Efforts have been made to eliminate the emetic potent ia l of PDE 4 inhibitors by developing compounds with decreased [,H) rolipram binding affinit y whit retaining POE 4 potenc/D

.

Rolipram Binding Site

The high affinity rolipram bind ing site IS an intriguing factor in the puzzle of POE 4 ac ti vity regulati on. It has been reported that hi gh affinity binding sites in the rat brain membrane are labeled by [,H) rolipram in a stereospec ific and stereose lec ti ve and saturabl e manner"". It has al 0 been di sclosed that a monocyte derived recombi nant PDE 4 has a binding site with an affi ni ty for ro lipram approximately 100 times that of cata lytic site'·28. Studies with other PDE inhibito rs that bind to catalytic domain ind icated the di sti nction of rolipram binding site. Recently, ev idence ind icat ing that roilpram binding site may not be allosteric but a part of a different conformer of POE 4 has appeared'.

Rolipram has frequently been used as a bas is for design of new and sUbtype specific POE 4 inhi bi tors. RO 20-1724, (4) ,2 is another potent compound containing the catechol ether moiety fo und in rolipram.

(4)

GUPTA el al.: SELECTIVE PHOSPHODIESTERASE 4 INH IBITORS 54 1

Severa l N-heterocyclic benzamide derivatives 5 , designed from rolipram have been demonstrated to show exceptional potency in histamine induced

bronchospasm and POE 4 inhibition . RP7340 I (6)" is a potent benzamide POE 4 inhibitor. It shows nonselectivity for inhibiting POE 4 (catal yti c s ite) over the disp lacement of rolipram from its binding site.

(5)

R = Cyclopentyl

/Het

HN

o

Het = 3,S-dichloro-pyrid-4-yl

0-0 CI H3co-b-CONH~

CI

(6)

Bacher e/ al. 34 synthes ized highly potent N­phenyl ro lipram derivative 7 with a hydrophilic substitution in 5 position of central phenyl ring.

(7)

Another group replaced 3-methoxy-4-cyclopenty loxy or catecho l like moiety with an indole

moiety producing compounds that potently inhibited the activation of inflammatory ce lls ill vitro' i. A series of conformationa ll y constrained qu arternary substituted oxindole de rivative of COP-840, a potent and se lect ive POE 4 inhibitor was a lso synthesized by thi s group's. Bioavailable and efficac ious 2-methoxy­benzimidazole based POE 4 inhibitors has also been evaluated by Regan et al. ' ·\6.

In a senes of 5-(catechol ethers)-2-imidazolidinones, compris ing structural features of

both rolipram (1) and RO 20-1724 (4), the subst ituents on catecho l-3-oxygen was primarily modified to get compound 8 and 9 (ref. 20).

R1" 0 N--( .::~NH

I CH3

R1 R2 R1 R2

(8) H 0- (10) CH3 1::2-CH3

(9) CH3 (11) CH3 h Another series containing bi , tri and tetracyclic

hydrocarbons at 3-alkoxy position of the same parent structure has a lso been studied; Compound 10 and 11 were the most potent inhibitors in this series2o.

Tetrahydro-pyrimidinone 12 was a lso prepared and was observed that two enantiomers were

equipotent. POA-64 L (13) was equipotent to rolipram as an inhibitor of dog trachealis POE 4.

542 J SCI INO RES VOL 62 JUNE 2003

~o o

I CH3 (13)

A novel senes of 4-(3-alkoxy-4-methoxy­phenyl)benzoic ac ids and their corresponding carboxamides have been prepared and evaluated in an effort to reduce emetic side effects' O Phenylpentoxy derivative (14) was found to exh ibit potent POE 4

inhibitory activ ity and possessed approximate ly 400 times weaker activ ity than ro lipram for CH] rolipram binding sit e and demonstrated a sign ificant red ucti on in emet ic s ide effects.

COOH (14)

Similar strategy led to the development of a potent second generat ion inhibitor of POE 4 with a dec reased potential for side effects. SB, 207499 (4-cyano-4-[3-( cyc lopenty lox y )-4-methox ypheny 1]­cyc lohexane- I-carboxy lic acid), ArifloTM (15)37

deve loped by Smithkline Beehcam, is presentl y undergoing phase II and III clinical tri a ls with respect to paed iatri c patients with asthma and patients with chronic obstruc tive pulmonary di sease, respective ly. It has a large therapeutic potenti a l and a decreased potential for side effec ts as compared to rolipram. It has been sugges ted that agents displaying potent cata lyti c s ite activity with a reduced activity at HARBS (hi gh affinity rol ipram binding s ite) would have good anti-inflammatory property with decreased potential to induce s ide effects and it has been es tab li shed th at ArifloTM di spl ays potent se lective

affi nities for POE 4 cata lytic s ite (lCso = 95 nm) and for HARBS CICso = 120 nm) compared to rolipram

which showed (IC50 value of 300 and 5 nm respect ive ly for POE 4 and H ARBS) , suggest ing it to di splay an improved the rapeut ic ac ti vity with low inci dence of side effec ts as compared to ro lipram.

[Yo COOH

o

I CH3

(15)

A series of rol ipram deriva ti ves diffe rently substituted e ithe r at the pyrrolidinone or at aromatic ring have been synthes ized and reporred1X

. A WO-12-28 1 (Lotepredno l), a 5-hydroxyindole derivative which has been developed by Cell tech has also been eval uated in pass ive ly sens iti zed human airways and prevented contraction in red uc ing allergen cha lle nge in sens iti zed guinea pig and Brown Norway rats3

.1')

Piclamilast, (POE 4 inhibitor) acts by down regul ati ng-tumour necros is factor and has shown potent anti-inflammatory activity ill vitro studies using novel human whole blood assay.

A nove l seri es of 2,2,-d isubstituted indan-I ,3-dione (16) based cyc li c compou nds a .

CH3

I o

o

o R

(16)

POE 4 inhibitors have been desc ribed . T hi s structura lly unique c lass of POE 4 inhibitors has conformationally constrained indan ring linker and led to the identification of inhibitors w ith nanomo lar potency, no emetic and oral activity" .

GUPTA e/ {I I .: SELECTIVE PHOSPHODIESTERAS E 4 INHIBITORS 543

Heterocyclics and Analogues

Th is c lass of PDE 4 inhibitors is exemplified by nitraquazone (2). The archetyp ical quinazolindione

moiety of compound 2 has been ex tensive ly manipu lated to affo rd a varie ty of structure der ived

compounds . 3'-N02 group of compound 2 has been replaced by different nonprotic , e lectron-withdrawing functiona lities li ke -CI, -Br, -COOCH3 to study SAR8

.

Corresponding ac id and N-methy l amide produced a substantial and compl ete loss . In potency

. ~ ?O respectl ve l y ,- .

Pyridopyrimidinedione ana logues have a lso been prepared . A lthough benzene-pyridine isosteric replacement led to decrease in potency in case of

compound 17 as compared to compound 18 but

introducti on of bu lkier groups at N3 afforded 19-21 with substantially inc reased potency. The corresponding 4-pyridy l de rivative 22 has proved to be four times potent inhibitor of PDE 4 wi th respect to prototype 1740

. Compounds of the type 23 containing pyridopyridazi none nucleus are nanomolar selecti ve inhibitors of PDE 441 . The concomitant

increase in side effects limited their development. Attempts were made to reduce these adverse effects and compounds were sy nthes ized by replacing pyridine w ith a series of he te rocyclic sys tems like pyrro le, pyrazo le, 1,2-dihydropyridine and th iophene 42.43 .

o

R1

X R1 R2

(17) N COOCH3 CH3

(18) CH COOCH3 CH3

(19) N COOCH3 phenyl

(20) N COOCH3 cyclopentyl

(21 ) N COOCH3 norbornyl

(22) N N02 4-pyridyl

o

(23)

These compounds showed s ignifi cantl y better balance between PDE 4 inhibition and emetic s ide effects. Further simplificati o n led to quino line deri vat i ve RS 14203 (24) wh ich is one of the mos t potent PDE 4 inhibito r.

(24)

(25)

Rep I acemen t of 3' nitropheny l group of compound 24 by benzot riazo le resulted in forma ti on of compound 25.

Naftiridinones 26 and compound 27 (ref. 8 and 44) result from a lesser structural s impli fication of nitraquazone. Heterocyc lic fused 3[2H]-4 pyridazinones 28 have been synthes ized and reported to have potent selective PDE 4 inhibitory act ivity and

544 J SCI IND RES VOL 62 JUNE 2003

greatly attenuated affinity for rolipram high affinity

b· d ' . 41 In IIlg site · .

N 0

)0 F

(26)

0

(28)

N::::"\ cC:xN

_

R

N N 0

6 (27)

0

c('NHM N a

Gtz (29)

Nicotinamide e the rs 29, ring opened variants of

pyridopyridindiones have recentl y aroused renewed inte rest in inhibiti on of POE 4. They also have reduced e metic s ide effec ts. These compounds were earlier reported in 199 145

. A variety of substituents Z = -F, -C!, -OCH" -CN, -CF, have been prepared. Meta and para positions were found to be favourabl e

b I . 4)

ut or(1 o was not favoured · . Recently , POE 4

inhibi to rs based on pyrido[2,3-dJpyrazino 30 backbone have been di sclosed46

,47.

(30)

A novel class of inhi bitors like compound 31 and 32 based on same guinoline. guinolone and naftiridinone template but a lso with the presence of carboxamido or sulfonamido groups have been reported48A9

.

R, R1 = cycloalkyl X= N, CH, CR1

(31 )

/RS X-N

""- R6

R

X= co, cs

(32)

Nitraguazone like inhibitors based on an almost flat heteroaromatic area generally formed by 6-6 condensed sys tem ; One (he tero) a romatic or a cycloalky l sys tems connected to flat porti on through a methyl ene spacer with an elect ron withdrawina

. R b

substituent represents the best pharmLlcophore model

33. Cha ll enge in this c lass of POE 4 inhibitors is to ha ve the se lect ive PDE 4 inhi bitory activity in nanomolar potency with strongly reduced affinity for high affinity ro lipram binding site to impro ve the the rapeutic index.

~0 N X

~ Y

(33)

GUPTA el al.: SELECTIVE PHOSPHODIESTERASE 4 INHI BITORS 545

A new type of bronchodi lator agents, bi- and tri-cyc li c nitroge n bridgehead co mpounds w ith a pyrimidine-4(3H)-one ring have been synthes ized and eva lu ated for bronchodilatory activity . One of the co mpounds was found as a potent bro nc hod i lator50

.

A series of nove l tricycli c he te rocyclics imidazo[4,5-c] [1 ,8] naphthyridin-4-(5H)-ones have been designed and synthesized4-l. Compound 34 re laxed spontaneous guinea pig isolated trachea l preparati on with 4- 16 fold greater potency than ami nophy lline . It a lso inhibited PDE 4

/H

roHN

\

::--...' N N 0

6 (34) (35)

New heterocycl ic compounds 3H-imidazo [ 4,5-c]qu inazo line-4(5H)-ones 35 have been designed by Suzuk i ef a l .51 Thi s tricyc lic hete rocyc lic can be regarded as a fu s ion compound of a benzene ring to the bond between 2 and 3 position of 7-substituted xanthine . 5-Ethyl-3-methyl derivative was fou nd to be 5-fo ld more active than theophylline for the ir protec ti ve effect aga inst antigen induced contraction of guinea pig trac hea.

Simi la rly , 7,5-di subst ituted I H-imidazo [ 4 ,5-c]quino lin-4[5H] -ones (36) were synthes ized and were tested as potent and act ive bronchod il ators. The most potent compound of thi s series showed weak POE 4 inhibiti on which could not account for its potent bronchodi lati on.

(36)

N~CH3 'S---yN

HN6 I"

.--:::

(37)

F rom the common phannacoph ore for nitraquazone re lated compounds, a se ri es o f novel heteroaromatic co mpounds have been designed, synthes ized and eva luated as PDE 4 inhi b itors. Thienopyrimidin (37) was selected a ~; a lead compound and a number of compounds with va ri ous li pophilic and aromat ic groups in bot h C-2 and C-4 pos iti on were synthesized. These compound s showed a good balance of PDE 4 act ivity and displcelllent of [.\H] rolipram from its binding s ite52

.

O rder of reacti vity of pte ridine carbon atoms

towards secondary am ines have been e luc id ated and

alkylami no substituted pterid ines 38 free of pos iti onal . I b I" Isomers l ave een preparec .. .

C) N CI

N:/" """

/\ ~ I h

L--.I H I ~

(38)

o

OH

(39)

6,8-0i substitutd-I ,7-naphthyridines (NVP-AB E 171 , 39 ), a new class of se lective phosphodi es te rase inhibitors has recently been repo rted 54 . 39 Has been found about 40-times more potent as compared to Ariflo (15). A series of l-aryl-2,3-bi (hydroxymeth yl) naphthalene lignan have been sy nthes ized and

546 J SCI IND RES VOL ('2 JUNE 2003

eva luated fo r the ir ability to se lectively inhibit PDE 4 in iso lated pi g tracheal strip . Replacement of I-phenyl ring by a pyridone ring led to marked improvement of the ir se lectivity for . PDE 4 over PDE 3. Compound 40 was chosen as candidate for further pharmacological evaluations5

.

A new approach to improve therapeutic window of PDE 4 inhibitors is aimed at the identification of the specifi c targets for emesis and efficacy. An e met ic, efficacious and competitive PDE 4 inhibitor 41 capable of cova lently tagging its biological targets upon photoactivation has been synthesized. Highly emetic and efficacious PDE 4 photoaffinity probe has been reported. Thi s probe would be highly useful for identification of respective targets through which PDE 4 specific inhibitors cause emesis and also produce the ir efficac/

6.

(40)

(41 )

Xanthine and Related Compounds

OH

OH

Theophylline represents this class of se lective PDE 4 inhibitors . Xanthines have long been known to

cause a variety of physiological effects. The CNS st imul atory properties of caffeine have been utili zed for centuries. Tachycardia and bronchod ilati on are other responses el icited by xanthines. Inhibiti on of phosphodiesterase in heart, brain and lungs may be the mechanism by which xanth ines exert thei r effects57

. Theophylline preparations have found continuous use as bronchodilators in the treatment of asthma for almost a century. It is a weak non­selec tive phosphodiesterase inhibitor, but it is bel ieved that PDE inhibitory activi ty may contribute to both its bronchodilatory and anti-inflammatory act ivities58

. Although theophylline is useful in the treatment of asthma, the value of theophylline is limited to a narrow therapeutic index due to wide range of gastrointestina l, CNS and cardiovascular side effects59

. The drugs that couple the efficacy of theophylline with an improved side effects profile and an increased therapeutic index would be an important advance in the treatment of asthma. Attempts have been made to improve therapeutic profil e by synthesizing new xanthine analogues without specifically focusing on PDE inhi bitory ac tivity but so far these efforts have not been successful.

An alternative approach towards developing an 'improved theophylline' has emerged recent ly. Using xanthine skeleton, attempts have been made to design and synthesize novel compounds wh ich are selective PDE 4 inhibitors and also retai n tt he therapeutic efficacy of theophylline. Xanthine nucleu present in theophylline is also present in the PDE substrate and will bind to and block highly conserved enzyme catalytic site. Miyamoto et al.60

,6 J studied SAR of this class and reported an interesting series of heterocyclic fu sed xanthines .

A series of xanthines with var ied substituents at the 1,3 and 8 positions have been prepared in order to understand the SAR for alkyl xanthines as inhibi tors of phosphodiesterase8

,62.

Many 7-alkylated deri vatives of theophyll ine such as dyphylline (42), doxophylline (43), th ioanalogue of doxophylline (44), proxyphylline (45), bamiphylline (46) , acephylline (47) and etophylline (48) have been synthes ized and studied5

,6J. Among the therapeu tically useful

synthetic xanthine analogues, dyphylline (42) has been approved and has appeared in the US market as an antiasthmatic drug. Bamiphylline (46) and

GUPTA el al.: SELECTIVE PHOSPHODIESTERASE 4 INH IBITORS 547

Doxophylline (43) have been marketed in Europe5,62.

These deri vat ives are generall y less active and exhibit low or moderate PDE 4 inhibitory activity than theophy lline but are stab le in soluti on and in vivo. T hese possess same side effects as theophylline.

o

H3C-i~~>-R' OANJlN

I CH3

R1 R2

(42) CH2CH(OH)CH20H H

o

(43) CH2 -< J H

o S

(44) CH2 -< J H

s (45) CH2CH(OH)CH3 H

(46) ICH,I, - NIC,HsHCH,l,OH CH,--o

(47) CH2COOH H

(48) CH2CH20H H

Denbufylline (49) is a se lecti ve PDE 4 inhibitor

show ing low adenosine receptor affinitl'64, but the

development of compou nd was discontinued because

of poor pharmacokinetics.

Arofy lline (50) is in phase ill clinical trial s for

oral asthma therap/5. It is a weak but select ive

inhibitor of PDE 4 as compared to theophylline.

R2 R3

CH2CH(OH)CH20H CH3

(50) pC1CsH4

It is 25-30 fo ld less emetic as compared to rolipram. Arofy lline demonstrated s ignificant improvement of pulmonary funct ion, as well as safe profile. Structural analogues of arophy lline have been reported by a ch irosc ience group. T he compounds showed improved ratio fo r PDE 4 inhibitory act ivity versus emetic side effects. Cipamphylline (51) (BRL 60063) was the prototype of a series of potent PDE 4 inhibitors reported and has been synthes ized by Smithkline Beecham66

. Sulfonation of c ipamphylline at 7- and 8-positions increased potency against PDE 5A as compared to PDE 4 isozymes. 8-substituted piperazine derivatives have been reported by Ragnier et at. 67 having a combi nation of antia llergic and antihi staminic propert ies. They also di splayed a potent bronchodilatory activ ity with enhanced duration of action. Among these, l-methyl-3-isobutyl-8-(4-benzhydrylpiperazinoethyl) xanthine S9795 (52) exh ibited inhibitory action on mast ce ll degranulation and phosphodiesterase enzyme8

.67

.

(51 )

(52)

A series of benzoseparated compounds purines, isoguanidines and thioxanthines whi ch inhibit PDE 4 from bovi ne tracheal smooth muscl e have been synthesized and reported. 68 Depending upon the subst ituents at C-7, C-8 or C- I positions, these

548 J SCI IND RES VOL 62 JUNE 2003

benzoseparated linear deri vat ives of 3-isobutyl-l­Ille thylxanthine 53 show POE inhibiting activity .

o

(53)

(54)

R" I 1

N Ir R'" N

One of the xanthine analogue, Ibudilast (54) , marketed as an oral ly act ing antiasthmatic druo in

H.W . .. b

Japan has been found to be a nonspecIfIc and moderate ly potent POE 4 inhibitor.

SCA 40 (55)70 is an effect ive bronchodilator in human bronchus precontracted with different spasmogens. The presence of bromjne on position 6 and an amino (a lkylamino) group on pos iti on 8 plays a criti ca l role in the activ ity. It also shows POE inhibitory activity in micromolar range. ICI-63197 (55) is another reported compound which is a weak selecti ve inhibitor of POE 4 71.

NHCH3

NJy}(N ~N

Br

(55) (56)

Efforts have been made to prepare hybrid struc tures of xanthine skeleton and rolipram. V 11294

A (57) 72 and RPR 132703 (58)73 are the most

inte resting examples .

(57) (58)

These compounds have progressed into phase If clin ical tri als for asthma.

Miscellaneous Selective PDE 4 Inh ibitors

POE 4 inhibitors based on benzofuran (59) and benzopyran (60) nucleus have been reponeds. (61) Showed POE 4 inhibitory activity in the nanomolar ranges. Indazol e (62)74 and pyrazo lo[3 ,4-c]pyridine

(63) represent varioLls other POE 4 inhibitors synthesized by Pfizer Labs7

) .

CH3

/ o

R

o /

CH3

~CH3

~ 0

0.. I CH3

NH 0 CIUI CI I"

,0 N

(60)

(59)

/CH:I o

He!

(61)

GUPTA et al.: SELECTIVE PHOSPHODIESTERASE 4 INHIB ITORS 549

VCI

N '"

I ~ N-C

H " CI 0

/J (62)

(63)

Benzodiazepine deri vati ves (64)76 represent novel POE 4 inhibitors with potent bronchodilatory acti vity. Recentl y, a novel series of pyridazinones and phthazinones (65) have also been reported as potent and selecti ve inhibitors of POE 4 10.

R

(64)

(65)

NH -c Het II o

Conclusions

With the development of selecti ve POE 4 inhibitors, interes t and exc itement has been generated to discover new cl asses of drugs fo r the treatment of asthma. Clinical experi ence with the use of isozymes selective POE 4 inhibitors for the treatment of as th ma

is limited. Determination of the utility of this novel

strategy currently be ing evaluated for asthma require

additional clinical studies. Although mechani sm of action, safety and continuous efficacy of POE 4 inhibitors on chronic use is still questi onabl e, it seems to be reasonable isozyme fo r continued evaluation as nove l bronchodi lators. Evidence is a lso mounting in support of POE 4 as a target for anti-infl ammatory agents. Combining POE 4 inhibitory ac ti vity with

POE 3 or POE 5 inhibitory ac ti vity within a single

molecule could lead to a very effective bronchodil ator with anti-infl ammatory acti vity, although there wi ll

also be increase in side effects.

No selecti ve POE 4 inhibitor is currently

marketed. Some of the selecti ve POE 4 inhibitors are in phase II and III clinical tria ls as anti as thmati c

agents. The recent discovery of two POE 4 conformers HPOE4 and LPOE4 with the ir unique

ti ssue di stribution and activity has further contributed

to des ign of new and specific inhibitors wi th

decreased side effects. It has been accepted that high

affinit y for HARBS is assoc iated with more

propensity to induce side effects. Thus high potency at catalytic site and reduced aff inity for HARBS wi th selectivity for POE 4 may affo rd the idea l

physiological and toxicological profile for drugs wi th

clinical efficacy in asthma. One such compound is SB207499 (ArifioTM) which is in the final stages of

clinical trials. Several POE 4 inhibitors based on the

modification of theophylline, ro lipram or

nitraquazone are currently undergoing evaluation and show much promise for future therapy of asthma.

Although the POE 4 inhibitory effec t of therapeutically useful antiasthmatic drugs , methylxanthines was initi all y considered as an important mechanism in the ir antiasthmatic acti vi ty,

but they generally di splay lower or moderate potency

at the catalytic site e.g. arofylline, a POE 4 inhibitor, is one of the most advanced drugs in cli nical evaluation. The mechani sm remains controvers ial and

550 J SCI IND RES VOL 62 JU E 2003

data suggest that for clinical efficacy in asthma

potency at cata lytic s ite of PDE 4 inhibitors is not an

essential requirement. To prove this , further,

development o f many potent PDE 4 inhibitors have

been discontinued as antiasthmatic agents in recent

years. Sti II the re is much promise remaining in the

research in the field.

Theophylline nucleus may be very useful for

desi gning new antiasthmatic drugs with inherent

antiasthmatic properti es of this old drug and

decreased cardiovascular and CNS s ide effects. On

the who le, selective PDE 4 inhi bitors, particularly

xanthines open a ve ry interesting prospective of a

breakthrough in thi s area of research for medicinal

chemi sts . The rational des ign of PDE 4 ' inhibitors has

taken on new meaning and vitality and now selective

PDE 4 inhibitors could be designed with a specific

the rapeutic endpoint for optimum clinical bene fit.

Acknowledgements

Th is re vi ew is the outcome of literature survey

fo r the research project entit led " De velopment of

antiasthmatic agents" financed by Haryana State

Counc il for Sc ience and Techno logy, Chandigarh ,

India. The support is gratefu lly acknow ledged . We

dedicate this work to our beloved teacher and guide

late Professor Dharam Paul lindal.

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