Novel, Potent, and Selective Phosphodiesterase-4 Inhibitors as Antiasthmatic Agents:  Synthesis and Biological Activities of a Series of 1-Pyridylnaphthalene Derivatives

Abstract

The structural requirements for potent and selective PDE4 inhibition were revealed in a 1-pyridylnaphthalene series, and the best compound (3kg, T-2585.HCl) was chosen for further biological evaluation (PDE4 inhibition IC50 = 0.13 nM, selectivity PDE3/4 ratio = 14 000). Compound 3kg showed potent antispasmogenic activities (ED50 = 0.063 mg/kg for reduction of antigen-induced bronchoconstriction, intravenously; ED50 = 0.033 mg/kg for reduction of histamine-induced bronchoconstriction, intraduodenally) in guinea pigs with little cardiovascular effects. Furthermore, 3kg induced significantly weaker emetic effects than RP73401 after oral administration in ferrets and intravenous administration in dogs (3kg, none of 4 ferrets vomited at a dose of 10 mg/kg, po and none of 8 dogs vomited at a dose of 0.3 mg/kg, iv; RP73401, 4 of 8 ferrets vomited at a dose of 3 mg/kg, po and 6 of 8 dogs vomited at a dose of 0.3 mg/kg, iv); that is compatible with the lower affinity for the high-affinity rolipram binding site (3kg, 2.6 nM; RP73401, 0. 85 nM). This may imply that 3kg has an improved therapeutic ratio because of a broad margin between the Ki value of binding affinity and the IC50 value of PDE4 inhibition (ratio = 0.050).

Antitumor Properties of Podophyllotoxin and Related Compounds

“…The importance of the lactone ring in the inhibition of the polymerisation of tubulin has been demonstrated [212][213][214]. When the lactone is replaced by a tetrahydrofuran ring, this gives rise to less active compounds and if the oxygen of the cyclic ether is replaced by CH 2 , S or SO 2 , the antineoplastic effect is reduced even further [215].…”

“…The methylenedioxy group may be important [213][214][215] in the pharmacological response since most lignans with antimitotic properties have it [231], although there are no conclusive studies in this sense [232]. Our research team have isolated several cyclolignans from Juniperus sabina and has been and is still envolved in the molecular manipulation of podophyllotoxin and related cyclolignans and nearly all of these derivatives have been evaluated for their antineoplastic activity.…”

PDE4 inhibitors 1999

“…Consistent with the hypothesis that the ratio of these two activities is predictive of emetic potential T-2585 was only found to induce emesis in ferrets at 100 mg/kg p.o. [30]. It has thus been reported as being progressed for further evaluation.…”

Phthalazin-1(2H)-one as a remarkable scaffold in drug discovery

“…They were M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 4 developed as enzyme inhibitors, such as aldose reductase (AR) inhibitors [7], poly(ADP-ribose)polymerase (PARP) inhibitors [8] or phosphodiesterase (PDE) inhibitors [9], as ligands acting at G protein-coupled receptors (GPCRs), in particular histamine receptors [10], adrenoceptors [11], dopamine/serotonin receptors [12], or adenosine receptors [13], or even as modulators of ion channel-coupled receptors [14] or ligands for nuclear receptors [15]. Thus, phthalazinone derivatives have a wide variety of biological properties like antidiabetic [16], anticancer [17], antiasthmatic [18], anti-inflammatory and analgesic [19], antihistaminic [20], antihypertensive and antithrombotic [21], anticonvulsant [22], antimicrobial [23], antiviral [24], antiparasitic [25], as well as antidepressant and antipsychotic activities [26,12]. Their use as diagnostic agents [27] or even as herbicides [28] was also described.…”

“…In addition, a series of 1-pyridylnaphthalene derivatives substituted with a heterocyclic moiety containing a carbonyl group was reported as a new class of potent and selective PDE4 inhibitors [18]. The best compound of this series was the phthalazinone analogue 64 ( Figure 10).…”