Discovery of novel 1,4-dihydropyridine-based PDE4 inhibitors

Poondra, Rajamohan R.; Nallamelli, Ratnam V.; Meda, Chandana Lakshmi T.; Srinivas, B. N.; Grover, Anushka; Muttabathula, Jyotsna; Voleti, Sreedhara R.; Sridhar, Balasubramanian; Pal, Manojit; Parsa, Kishore V. L.

doi:10.1016/j.bmcl.2012.11.121

Cited by 24 publications

(7 citation statements)

References 22 publications

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“…This interesting effect may be related to the chemical structure of these compounds because diverse chemical moieties of rolipram, 4NO2PDPMe or 4APDPMe are very similar to various very well-known specific Ca 2+ –channel blockers, such as nifedipine, verapamil, diltiazem and indomethacin, which are structurally similar to diverse PDE-4 inhibitors [16] and to different chemical families of Ca 2+ -channel blockers that relax smooth muscle regardless of the contraction stimulant [26] (see Figure 7). Indeed, novel 1,4-dihydropyridine-based (similar to nifedipine and nicardipine molecules) PDE-4 inhibitors, which share many functional groups, have been described [53]; moreover, the number of reports disclosing the effects of PDE-4B inhibitors on Ca 2+ –channel blockage has recently increased [54]. Because thalidomide analogs are much less potent than specific Ca 2+ –channel blockers, they may not pose a risk of cardiovascular side effects [1,3,4].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Uterine Contractility by Thalidomide Analogs via Phosphodiesterase-4 Inhibition and Calcium Entry Blockade

et al. 2016

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Uterine relaxation is crucial during preterm labor. Phosphodiesterase-4 (PDE-4) inhibitors have been proposed as tocolytics. Some thalidomide analogs are PDE-4 inhibitors. The aim of this study was to assess the uterus-relaxant properties of two thalidomide analogs, methyl 3-(4-nitrophthalimido)-3-(3,4-dimethoxyphenyl)-propanoate (4NO2PDPMe) and methyl 3-(4-aminophthalimido)-3-(3,4-dimethoxyphenyl)-propanoate (4APDPMe) and were compared to rolipram in functional studies of spontaneous phasic, K + -induced tonic, and Ca 2+ -induced contractions in isolated pregnant human myometrial tissues. The accumulation of cAMP was quantified in HeLa cells. The presence of PDE-4B2 and phosphorylated myosin light-chain (pMLC), in addition to the effect of thalidomide analogs on oxytocin-induced pMLC, were assessed in human uterine myometrial cells (UtSMCs). Thalidomide analogs had concentration-dependent inhibitory effects on spontaneous and tonic contractions and inhibited Ca 2+ -induced responses. Tonic contraction was equipotently inhibited by 4APDPMe and rolipram (IC 50 = 125 ± 13.72 and 98.45 ± 8.86 µM, respectively). Rolipram and the thalidomide analogs inhibited spontaneous and tonic contractions equieffectively. Both analogs increased cAMP accumulation in a concentration-dependent manner (p < 0.05) and induced changes in the subcellular localization of oxytocin-induced pMLC in UtSMCs. The inhibitory effects of thalidomide analogs on the contractions of pregnant human myometrium tissue may be due to their PDE-4 inhibitory effect and novel mechanism as calcium-channel blockers.

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Section: Discussionmentioning

confidence: 99%

Inhibition of Uterine Contractility by Thalidomide Analogs via Phosphodiesterase-4 Inhibition and Calcium Entry Blockade

et al. 2016

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“…90 With the combination of dimethoxybenzene, indole, and dihydropyridine, compound 37 (Figure 16) was found to be a potent PDE4 inhibitor with IC 50 values of 0.54 and 0.65 nM for PDE4B and PDE4D, respectively. 91 The docking of 37 to PDE4B/PDE4D showed that its indole moiety has two possible orientations in PDE4D and forms hydrogen bonds with Glu396 or Glu505, whereas 37 exhibits a completely different orientation in PDE4B and forms a hydrogen bond with Ser442. The dimethoxy groups of 37 interact with the metal ions in PDE4B, and the indole moiety forms hydrogen bonds to Gln443.…”

Section: Survey Of Pde4 Inhibitorsmentioning

confidence: 99%

Advances in the Development of Phosphodiesterase-4 Inhibitors

Peng

et al. 2020

J. Med. Chem.

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Cyclic nucleotide phosphodiesterase 4 (PDE4) specifically hydrolyzes cyclic adenosine monophosphate (cAMP) and plays vital roles in biological processes such as cancer development. To date, PDE4 inhibitors have been widely studied as therapeutics for the treatment of various diseases such as chronic obstructive pulmonary disease, and many of them have progressed to clinical trials or have been approved as drugs. Herein, we review the advances in the development of PDE4 inhibitors in the past decade and will focus on their pharmacophores, PDE4 subfamily selectivity, and therapeutic potential. Hopefully, this analysis will lead to a strategy for development of novel therapeutics targeting PDE4.

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“…In recent research [ 78 ], authors disclosed that PDE4B selectivity can be achieved by the capture of a C-terminal regulatory helix, known as CR3 (control region 3), across the active site in a conformation that closes access by cAMP. PDE4B selectivity is driven by a single amino acid polymorphism in CR3 (Leu674 in PDE4B1 versus Gln594 in PDE4D).…”

Section: Selective Pde4b Inhibitorsmentioning

confidence: 99%

Selective Phosphodiesterase 4B Inhibitors: A Review

Azam¹

2014

Sci. Pharm.

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Phosphodiesterase 4B (PDE4B) is a member of the phosphodiesterase family of proteins that plays a critical role in regulating intracellular levels of cyclic adenosine monophosphate (cAMP) by controlling its rate of degradation. It has been demonstrated that this isoform is involved in the orchestra of events which includes inflammation, schizophrenia, cancers, chronic obstructive pulmonary disease, contractility of the myocardium, and psoriatic arthritis. Phosphodiesterase 4B has constituted an interesting target for drug development. In recent years, a number of PDE4B inhibitors have been developed for their use as therapeutic agents. In this review, an up-to-date status of the inhibitors investigated for the inhibition of PDE4B has been given so that this rich source of structural information of presently known PDE4B inhibitors could be helpful in generating a selective and potent inhibitor of PDE4B.

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Discovery of novel 1,4-dihydropyridine-based PDE4 inhibitors

Cited by 24 publications

References 22 publications

Inhibition of Uterine Contractility by Thalidomide Analogs via Phosphodiesterase-4 Inhibition and Calcium Entry Blockade

Inhibition of Uterine Contractility by Thalidomide Analogs via Phosphodiesterase-4 Inhibition and Calcium Entry Blockade

Advances in the Development of Phosphodiesterase-4 Inhibitors

Selective Phosphodiesterase 4B Inhibitors: A Review

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