Journal of Scientific & Indu strial Research Vol. 62, June 2003, pp 537-553 Selective Phosphodiesterase 4 Inhibitors - Emerging Trends in Astluna Therapy (Antiasthmatics-3) Ranju Gupta*, Oeepika Gandhi and Oharam Paul Jindal University In stitute of Pharmaceuti cal Sciences, Panjab Universit y, Chandigarh 160014 Considerable interest has been generated in th e potential utility of isozyme selective inhibitors of phosph odiesterases 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 attractive targets for medicinal chemi sts. To date at least II different fami lies of POE isozymes are known, among which POE 4 plays a major rol e in mod ul ating the activity of virtu ally all cell s involved in the inflammatory process. In hibitors of thi s enzyme family display impressive antiasthmatic ac ti vity by red ucing th e bronchial smooth mu scle tone and consid erable anti-inflammatory activity. The review details th e various classes of POE 4 inhibitors stru cturall y related to rolipram, nitraquazone and xa nthines, 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 th e treatment of asthma is also discussed. Key words: Phosphodiesterase 4 inhibitors, Asthma therapy, Antiasthmatics, Isozyme, Rol ipram, Nitraquazonc. Xanthincs. Introduction Phosphodiesterase Superfamily There has been growing interest in recent years At least e leven different fami li es of POE tn the utility of selective phosphodiesterase (POE) isozymes are known based on the ir substrate inhibitors as novel targets for drug d iscovery. specificity (cAMP or cGMP) kinetics, and th e ir Phosphodiesterases compri se a heterogenous group responsi veness to a ll osterics modulator and of isozymes which differ neverthe less in their e ndogenous or exogenous regulators 1-9 (Table I). kinetic and physical characteristics, substrate Each POE fam il y in c ludes subfamilies that are (cAMP or cGMP) selectivities, sensitivity to e ncoded by distinct genes but have 70-80 per cent e nd ogenous activators, susceptibility and response homology with one anoth er and finally contain to phosphorylation by protein kinase, tissue several members. The fami Ii es of POEs are re ferred l distribution and subce llular locali zation -, . These by Arabic nume ral s (1-10), subfamilies by capital isozymes hydrolyse the 3'-phosphodiester bond of letters (A-D) and members by Arabic numeral s (1-3). cyclic messengers cAMP or cGMP to their inactive Nearly all these different POEs have unique primary S'-nucleotide forms. cAMP and cGMP are sequence in the ir catalytic or regulato ry domains and ubiquitous intracellular second messengers which they are often selectively expressed. This implies that playa promin e nt role in the regulation of important it may be possible to modulate individual isozymes using specific drugs. The differing distribution of cellular fu nctio ns such as secretion, contraction, POEs between cell types, the large diversity in metabolism and growth. T he e levation of their structure, function and regulation among POE intrace llular levels by POE inhibitors represents a isozymes makes it possible to develop selective and useful strategy for eliciting a variety of possibl y the rapeutically useful inhibitors and pharmacologica l effects. activators of individual isozymes, which will be devoid of unnecessary side effects. A number of * Author for correspondence inhibitors of phosphodiesterase isozymes have been ranju29in @yahoo.co.in described). They can be used as cardiotonics, 538 J SC I IND RES VOL 62 JU E 2003 Tab i<.: 1- Charactcri sti cs of ph os ph odiesterase isozyme families. mediators, cytoki nes and growth factors. Acute Famil y Isozyme Binding Specific Loca li zation airway obstlUction, bronchial hyperresponsiveness (s ubfalllil y) spec ifi cit y inhibitors ancl inflammatory state of bronchial mucosa with increased level of inflammatory mediators I(A .B.C) Calciulll/ cA MP or Vinpocetine. Nerve ti ss ue. cha racteri se this pathology. Eosin ophil s also playa calmodulin cGMP phenothi azine mast cell s. stilllulated tracheal prominent role in asthma sugge ting it to be an 8 11 epithelium. inflammatory disorder . Today asthma is affecting T cells over 5 per cent of th e adu lt populat ion and perhaps 2A( I-:l) cGMP Low affinit y Erythro[ hydrox Plat elets, upto 10 per cent of children. It is rising in prevalence, stilllulated fo r cA MP yl-nonyl] - endothelium, and cGMP adenine Illacrophagcs severity and mortalit y in the devel oping countries :l(A. B) cGMP Hi gh Si guazodan, SlIlooth lIluscle, despite substan ti al in crease in number of newer H inhibited affinit y for cil ostazo l. T cel ls. basophils. antiasthmatic agents . Many clas ses of dru gs like cAMP lIlilrinone. macrophagcs. leu kotriene receptor antagon ists, 5- 1i pox ygenase cil ostamide epithelial cells. adipocytes inhibitors, adenosin e antagonists. 'l11ti cholinergics , ~ 2 -ago ni s t s, glucocorti coid s and an tihi stamines are 4(A.B.CD) cAMP High RO-20- 1724. Inflammatory 15 II spec ifi c affinit y for ro li pralll. cells. neuronal al so used as effecti ve bronchodiiators· . cA MP CDP-8 .J O. ti ss ue ~ 2 Ad r e n ocepto r agonists are wid ely used in asthma SB -207499, therapy and on inhalation prod uce in stant RP-7J40 1 bronchodilation. They however have littl e effect on SeA) cGMP Hi gh Za prinast. Platelets. lu ng specifi c aflinity for S K&F-962:l 1; epithelia l cells underl ying inflammation and becau - of thi s reason cGMP dipyridilllolc their regul ar and long term use has been debated 8. 12-15 . 6(A.B.CD) Photo- Hi gh for Dipyridilllole. Retinal rod s and Systemic side effects such as tac hycard ia, pa lpitatio n recept or cGMP, Iow za prinast cones and headache are observed with inh aled B­ for cAMP adrenoceptor agoni sts and also the self-admin istration 7(A. B,CD) Rolipmm Hi gh None T cells, B cell s. of inhaled drugs may be difficult for old and disabled insensiti ve aflinity for skeletal mu scle. cAMP hean persons. Glucocorticoid s on the other hand have we ll documented anti-inflammatory properties and can reduce ai rway hyperresponsiveness bu t lack ant ithrombotic agents, vascul ar and airway smooth l 2 immedi ate bronchodilatory action . Chron ic muscle relaxants, anti-i nfl ammatory agents and administrati on of glucocorticoids can cause antidepressants. The knowledge that - (a) multiple significant suppression of hypothalamu s pituitary distin ct POE isozymes ex ist, (b) Isozymes differ in adrenal (HPA) ax is and of bone growth in children. It their cellular di stribution ancl synthesis of a variety of may also affect di sease progression. Two detai led inhibitors possessing marked degree of selectivity for 16 17 reviews have been publi shed by l indal ei al. on one isozyme over other, raises the possibility th at the Bradrenoceptor agoni sts and methylxant hines as unfavourabl e side effects profil e of nonselecti ve POE antiasthmati cs. in hibitors can be reduced by sy nthesizing compounds that are targeted specifical ly for the isozymes that Novel ora ll y acti ve anti asthmat ic drugs whi ch predominates in the particular tissue or th e cell of di splay both bro nchod il atory and an ti -infl ammatory I. nterest to . profile with reduced side effects and also wh ich can Recently, selective phosphodiesterase inhibitors substitute the combined therapy of inhaled B2- have received considerable attention ' as molecul ar receptor agonists (bronchodi lators) and targets fo r the development of antiasthmat ic agents. cort icosteroid s (anti-inflammatory) is the need of Several comprehensive reviews have been published hour. One class of drugs, whi ch we can look forward recently on the use of POE 4 inhibitors in the for effective as thma therapy with both treatment of asthma3.7.8. 11 .12. bronchodil atory and glucocorticoid like anti- infl ammatory property can be selecti ve Phosphodiesterase Inhibitors in Asthma ph osphodiesterase inhibitors. Phosphodiesterase Bronchial asthma is a noninfecti ous respiratory (POE) inhibitors result in enhanced intracellu lar x12 pathology invo lving the concerted actions of multiple levels of second messengers cAMP and cGMp . , in flammatory cell s, spasmogens, infl ammatory which are generall y associated with dampening GUPTA e/ al.: SELECTIVE PHOSPHODIESTERAS E 4 I HIBITORS 539 effects on airway smooth mu scl e. cAMP suppresses of selec ti ve ph osph odi esterase 4 inhibitors. First, the ac ti vation and medi ator release from th ere is general conviction th at th e du al anti­ infl ammatory cell s' 2.'8.,'J (Figure I ). These mediate infl ammatory and bronchodi latory profile of POE 4 the fun cti onal res ponses of ce ll s to a mu ltitude of inhibitors could lead to th e discovery of new agents hormones, neurot ransmitters and autoco id s with able to compete and perhaps to repl ace respect to the regul atory functi on of cell s in vo lved in corti costeroid s (ant i-inflammatory) and ~ 2 ago ni sts (bronochodil ators), the bas ic th erapeut ic agents for path ophys iology of asthma. So POE inhibitors have a th e management of as thma and second , new and theoreti cal advantage over the use of other promlsll1 g therapeutic appl ications of POE 4 anti as thmati c agents th at in hi bit th e formation or inhibitors in certain autoimmune di seases, e.g., antago ni ze the action of indi vidual mediators.