phosphodiesterase-in-2

Phosphodiesterase-IN-2 (Compound C7) is an orally active and selective inhibitor of phosphodiesterase 10A (PDE10A), with an IC50 of 11.9 nM. It enhances hepatic microsomal stability and reduces blood-brain barrier permeability. Phosphodiesterase-IN-2 exhibits favorable pharmacokinetic properties in mouse models and can alleviate isoprenaline-induced cardiac hypertrophy.

CP 461 (UNII-68OJX9I7DT), a specific PDE2A inhibitor, is a novel pro-apoptotic compound that inhibits cyclic GMP phosphodiesterase but not cyclooxygenase-1 or -2. CP 461 inhibits the growth of a variety of human tumor cell lines in vitro and selectively induces apoptosis in cancer cell lines, but not in normal cells.

Sulindac (Sulindac sulfoxide) is a sulfinylindene derivative prodrug with potential antineoplastic activity. Converted in vivo to an active metabolite, sulindac, a nonsteroidal anti-inflammatory drug (NSAID), blocks cyclic guanosine monophosphate-phosphodiesterase (cGMP-PDE), an enzyme that inhibits the normal apoptosis signal pathway; this inhibition permits the apoptotic signal pathway to proceed unopposed, resulting in apoptotic cell death.

EHNA hydrochloride is a selective inhibitor of cyclic nucleotide phosphodiesterase 2 (PDE2) and adenosine deaminase (ADA) with anticancer activity, increasing intracellular adenosine concentration in a treatment time-dependent manner. EHNA hydrochloride inhibits PHA and NaI04 mitogenesis.

PDE2/PDE10-IN-1 is an inhibitor of phosphodiesterase 2 (PDE2) and PDE10, with IC50 values of 29 nM and 480 nM, respectively.

EHNA is a potent and selective dual inhibitor of cyclic nucleotide phosphodiesterase 2 (PDE2) (IC50 = 4 μM) and adenosine deaminase (ADA). It exhibits concentration-dependent inhibition of cGMP-stimulated PDE2 activity, with IC50 values of 0.8 μM in humans and 2 μM in porcine myocardium, but shows limited inhibition on unstimulated PDE2. EHNA is involved in modulating various pharmacological responses, such as antiviral, antitumor, and antiarrhythmic effects.

NPP1-IN-2 (compound 3h) is a potent and selective inhibitor of ectonucleotide pyrophosphatase/phosphodiesterase-1 (NPP1), with IC50 values of 0.55 µM for NPP1 and 3.73 µM for NPP3.

PDE7-IN-2 is an inhibitor of phosphodiesterase 7 (IC50 = 2.1 µM) and can be used in Parkinson's disease studies.

DNS-8254 is a potent and selective Phosphodiesterase 2 (PDE2) inhibitor for the treatment of Memory Disorders (hPDE2a IC50 = 8 nM, Rat Cl-int = 25.6 uL/min/mg). DNS-8254 demonstrated significant memory enhancing effects in a rat model of novel object reco

O-Demethyl apremilast is an active metabolite of the phosphodiesterase 4 (PDE4) inhibitor apremilast .1It inhibits the activity of PDE4 isolated from U937 cells and LPS-induced TNF-α production in isolated human peripheral blood mononuclear cells (PBMCs; IC50s = 8.3 and 5.6 μM, respectively). O-Demethyl apremilast is also an oxidative degradation product of apremilast.2,3 1.Hoffmann, M., Kumar, G., Schafer, P., et al.Disposition, metabolism and mass balance of [14C]apremilast following oral administrationXenobiotica41(12)1063-1075(2011) 2.Lu, Y., Shen, X., Hang, T., et al.Identification and characterization of process-related substances and degradation products in apremilast: Process optimization and degradation pathway elucidationJ. Pharm. Biomed. Anal.14170-78(2017) 3.Bhole, R.P., Naksakhare, S.R., and Bonde, C.G.A stability indicating HPTLC method for apremilast and identification of degradation products using MS/MSJ. Pharm. Sci. & Res.11(5)1861-1869(2019)

3,3'-((2-Chlorophenyl)methylene)bis(4-hydroxy-2H-chromen-2-one) is a non-nucleotide inhibitor of ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1; Ki = 50 μM).1,2 It also inhibits urease (IC50 = 84.53 μM for the Jack bean enzyme).3 |1. Choudhary, M.I., Fatima, N., Khan, K.M., et al. New biscoumarin derivatives-cytotoxicity and enzyme inhibitory activities. Bioorg. Med. Chem. 14(23), 8066-8072 (2006).|2. Onyedibe, K.I., Wang, M., and Sintim, H.O. ENPP1, an old enzyme with new functions, and small molecule inhibitors - A STING in the tale of ENPP1. Molecules 24(22), E4192 (2019).|3. Khan, K.M., Iqbal, S., Lodhi, M.A., et al. Biscoumarin: New class of urease inhibitors; economical synthesis and activity. Bioorg. Med. Chem. 12(8), 1963-1968 (2004).

Quazinone is a selective inhibitor of phosphodiesterase 3 (PDE3) with positive inotropic and vasodilating properties. It induces relaxation of precontracted isolated human cavernous smooth muscle (IC50 = 4.2 μM), increases myocardial contractile force in anesthetized open-chest dogs in a dose-dependent manner (10-300 μg/kg), decreases systolic and diastolic blood pressure, and inhibits DNA synthesis induced by the PDGF isoform PDGF-BB in bovine coronary artery smooth muscle cells in a concentration-dependent manner.

Lodenafil carbonate, a prodrug dimer that delivers Lodenafil in vivo, is an orally active inhibitor of phosphodiesterase type 5 (PDE5), indicated for the treatment of erectile dysfunction (ED)[1][2].

PF-04449613 is a phosphodiesterase 9A (PDE9A) inhibitor (IC50= 22 nM).1It is selective for PDE9A over PDE1C (IC50= >1,000 nM), as well as over a variety of other PDEs, inhibiting PDE2-8, -10, and -11 activity by less than 30% in a panel of enzymes, ion channels, and transporters at 1 μM but does inhibit the human dopamine transporter (DAT; Ki= 293 nM). PF-04449613 (0.1-100 mg/kg, s.c.) increases cerebrospinal fluid (CSF) levels of cyclic GMP (cGMP) in rats. Subcutaneous administration of PF-04449613 (10 mg/kg) increases the rate of dendritic spine formation and elimination in mouse primary motor cortex pyramidal neuronsin vivo.2It increases the average running speed of mice in an accelerating rotarod task, indicating improved motor learning, at the same dose. 1.Claffey, M.M., Helal, C.J., Verhoest, P.R., et al.Application of structure-based drug design and parallel chemistry to identify selective, brain penetrant, in vivo active phosphodiesterase 9A inhibitorsJ. Med. Chem.55(21)9055-9068(2012) 2.Lai, B., Li, M., Hu, A., et al.The phosphodiesterase 9 inhibitor PF-04449613 promotes dendritic spine formation and performance improvement after motor learningDev. Neurobiol.78(9)859-872(2018)

CAY10761 is an inhibitor of ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1; IC50s = 467 and 429 μM for the human and snake venom enzymes, respectively).1,2 It also inhibits mushroom tyrosinase (Ki = 1.9 μM) and urease from jack bean, P. mirabilis, and B. pasteurii (IC50s = 0.093, <0.125, and 0.089 mM, respectively, at pH 8.2).3,4 |1. Khan, K.M., Fatima, N., Rasheed, M., et al. 1,3,4-Oxadiazole-2(3H)-thione and its analogues: A new class of non-competitive nucleotide pyrophosphatases/phosphodiesterases 1 inhibitors. Bioorg. Med. Chem. 17(22), 7816-7822 (2009).|2. Onyedibe, K.I., Wang, M., and Sintim, H.O. ENPP1, an old enzyme with new functions, and small molecule inhibitors - A STING in the tale of ENPP1. Molecules 24(22), E4192 (2019).|3. Ghani, U., and Ullah, N. New potent inhibitors of tyrosinase: Novel clues to binding of 1,3,4-thiadiazole-2(3H)-thiones, 1,3,4-oxadiazole-2(3H)-thiones, 4-amino-1,2,4-triazole-5(4H)-thiones, and substituted hydrazides to the dicopper active site. Bioorg. Med. Chem. 18(11), 4042-4048 (2010).|4. Amtul, Z., Rasheed, M., Choudhary, M.I., et al. Kinetics of novel competitive inhibitors of urease enzymes by a focused library of oxadiazoles/thiadiazoles and triazoles. Biochem. Biophys. Res. Commun. 319(3), 1053-1063 (2004).

Olprinone Hydrochloride, also known as Loprinone, is a phosphodiesterase (PDE) 3 potent inhibitor, exhibiting IC50 values of 150, 100, 0.35, and 14 μM for PDE1, PDE2, PDE3, and PDE4, respectively. It is utilized in heart failure research for its positive inotropic and vasodilative properties. It also exhibits anti-inflammatory activity [1] [2].

Theophylline (1,3-Dimethylxanthine) sodium glycinate is a potent phosphodiesterase (PDE) inhibitor that targets PDE3 to relax airway smooth muscle and is used in asthma and chronic obstructive pulmonary disease (COPD) research. It also functions as an adenosine receptor antagonist, histone deacetylase (HDAC) activator, and exhibits anti-inflammatory activity by increasing IL-10 levels and inhibiting NF-κB nuclear import, while inducing apoptosis [1] [2] [3] [4] [5].

PDE4-IN-11 is a potent phosphodiesterase isoenzyme 4 (PDE4) inhibitor, exhibiting remarkable bronchodilatory and anti-inflammatory characteristics. It is specifically designed for studying obstructive or inflammatory airway diseases [1] [2] [3].

Hcyb1 is a potent and specific inhibitor of phosphodiesterase 2 (PDE2). It exhibits a high degree of selectivity for inhibiting PDE2A with an IC50 value of 0.57 μM. In addition, Hcyb1 displays over 250-fold selectivity against other recombinant members of the PDE family. Moreover, its pharmacological actions include neuroprotective and antidepressant-like effects, which are believed to be mediated through the cAMP/cGMP-CREB-BDNF signaling pathway [1].

LEO-29102 is a potent, selective, and soft-drug phosphodiesterase 4 (PDE4) inhibitor, which may be potentially useful for treatment of dermatological diseases. LEO 29102 shows properties suitable for patient-friendly formulations giving efficient drug delivery to the skin. LEO-29102 has reached phase 2 and demonstrated clinically relevant efficacy in the treatment of atopic dermatitis.

CALP1 TFA, a calmodulin (CaM) agonist with a dissociation constant (Kd) of 88 µM, selectively binds to the CaM EF-hand/Ca2+-binding site, inhibiting calcium channel opening. This action blocks calcium influx and apoptosis with an IC50 of 44.78 µM, modulates glutamate receptor channel activity, and impedes a store-operated nonselective cation channel. Additionally, CALP1 TFA enhances CaM-dependent phosphodiesterase activity, denoting its multifaceted role in modulating cellular calcium dynamics [1] [2] [3] [4].

Phosphodiesterase 2 (II), a key enzyme prominently involved in the hydrolysis of vital second messengers, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), is frequently utilized in biochemical research. This enzyme is expressed across various tissues including the adrenal medulla, brain, heart, platelets, macrophages, and endothelial cells, playing a significant role in the regulation of diverse intracellular processes [1].

Sphingomyelin phosphodiesterase, a hydrolase, plays a crucial role in sphingomyelin metabolism by catalyzing the conversion of sphingomyelin into phosphocholine and ceramide. Furthermore, it is instrumental in cellular differentiation, immune and inflammatory responses, as well as intracellular cholesterol trafficking and metabolism [1] [2].

PDE7-IN-3 (Example 2) serves as an inhibitor of phosphodiesterase PDE7 and exhibits potential analgesic properties. It is applicable in the research of various pain types including inflammatory, neuropathic, visceral, and nociceptive pain [1].