dihydropyridines and Osteoarthritis

dihydropyridines has been researched along with Osteoarthritis* in 2 studies

Other Studies

2 other study(ies) available for dihydropyridines and Osteoarthritis

Article	Year
Discovery of potent, selective, bioavailable phosphodiesterase 2 (PDE2) inhibitors active in an osteoarthritis pain model, part I: transformation of selective pyrazolodiazepinone phosphodiesterase 4 (PDE4) inhibitors into selective PDE2 inhibitors. Bioorganic & medicinal chemistry letters, 2013, Jun-01, Volume: 23, Issue:11 We identified potent, selective PDE2 inhibitors by optimizing residual PDE2 activity in a series of PDE4 inhibitors, while simultaneously minimizing PDE4 activity. These newly designed PDE2 inhibitors bind to the PDE2 enzyme in a cGMP-like mode in contrast to the cAMP-like binding mode found in PDE4. Structure activity relationship studies coupled with an inhibitor bound crystal structure in the active site of the catalytic domain of PDE2 identified structural features required to minimize PDE4 inhibition while simultaneously maximizing PDE2 inhibition. Topics: Animals; Azirines; Binding Sites; Catalytic Domain; Crystallography, X-Ray; Cyclic Nucleotide Phosphodiesterases, Type 2; Cyclic Nucleotide Phosphodiesterases, Type 4; Dihydropyridines; Disease Models, Animal; Drug Evaluation, Preclinical; Osteoarthritis; Phosphodiesterase 4 Inhibitors; Phosphodiesterase Inhibitors; Protein Binding; Structure-Activity Relationship	2013
Discovery of potent selective bioavailable phosphodiesterase 2 (PDE2) inhibitors active in an osteoarthritis pain model. Part II: optimization studies and demonstration of in vivo efficacy. Bioorganic & medicinal chemistry letters, 2013, Jun-01, Volume: 23, Issue:11 Selective phosphodiesterase 2 (PDE2) inhibitors are shown to have efficacy in a rat model of osteoarthritis (OA) pain. We identified potent, selective PDE2 inhibitors by optimizing residual PDE2 activity in a series of phosphodiesterase 4 (PDE4) inhibitors, while minimizing PDE4 inhibitory activity. These newly designed PDE2 inhibitors bind to the PDE2 enzyme in a cGMP-like binding mode orthogonal to the cAMP-like binding mode found in PDE4. Extensive structure activity relationship studies ultimately led to identification of pyrazolodiazepinone, 22, which was >1000-fold selective for PDE2 over recombinant, full length PDEs 1B, 3A, 3B, 4A, 4B, 4C, 7A, 7B, 8A, 8B, 9, 10 and 11. Compound 22 also retained excellent PDE2 selectivity (241-fold to 419-fold) over the remaining recombinant, full length PDEs, 1A, 4D, 5, and 6. Compound 22 exhibited good pharmacokinetic properties and excellent oral bioavailability (F=78%, rat). In an in vivo rat model of OA pain, compound 22 had significant analgesic activity 1 and 3h after a single, 10 mg/kg, subcutaneous dose. Topics: Analgesics; Animals; Azepines; Azirines; Binding Sites; Catalytic Domain; Crystallography, X-Ray; Cyclic Nucleotide Phosphodiesterases, Type 2; Dihydropyridines; Disease Models, Animal; Drug Evaluation, Preclinical; Half-Life; Osteoarthritis; Phosphodiesterase 4 Inhibitors; Phosphodiesterase Inhibitors; Protein Binding; Pyrazoles; Rats; Structure-Activity Relationship	2013

Article

Year

Discovery of potent, selective, bioavailable phosphodiesterase 2 (PDE2) inhibitors active in an osteoarthritis pain model, part I: transformation of selective pyrazolodiazepinone phosphodiesterase 4 (PDE4) inhibitors into selective PDE2 inhibitors.

Bioorganic & medicinal chemistry letters, 2013, Jun-01, Volume: 23, Issue:11

We identified potent, selective PDE2 inhibitors by optimizing residual PDE2 activity in a series of PDE4 inhibitors, while simultaneously minimizing PDE4 activity. These newly designed PDE2 inhibitors bind to the PDE2 enzyme in a cGMP-like mode in contrast to the cAMP-like binding mode found in PDE4. Structure activity relationship studies coupled with an inhibitor bound crystal structure in the active site of the catalytic domain of PDE2 identified structural features required to minimize PDE4 inhibition while simultaneously maximizing PDE2 inhibition.

Topics: Animals; Azirines; Binding Sites; Catalytic Domain; Crystallography, X-Ray; Cyclic Nucleotide Phosphodiesterases, Type 2; Cyclic Nucleotide Phosphodiesterases, Type 4; Dihydropyridines; Disease Models, Animal; Drug Evaluation, Preclinical; Osteoarthritis; Phosphodiesterase 4 Inhibitors; Phosphodiesterase Inhibitors; Protein Binding; Structure-Activity Relationship

2013

Discovery of potent selective bioavailable phosphodiesterase 2 (PDE2) inhibitors active in an osteoarthritis pain model. Part II: optimization studies and demonstration of in vivo efficacy.

Bioorganic & medicinal chemistry letters, 2013, Jun-01, Volume: 23, Issue:11

Selective phosphodiesterase 2 (PDE2) inhibitors are shown to have efficacy in a rat model of osteoarthritis (OA) pain. We identified potent, selective PDE2 inhibitors by optimizing residual PDE2 activity in a series of phosphodiesterase 4 (PDE4) inhibitors, while minimizing PDE4 inhibitory activity. These newly designed PDE2 inhibitors bind to the PDE2 enzyme in a cGMP-like binding mode orthogonal to the cAMP-like binding mode found in PDE4. Extensive structure activity relationship studies ultimately led to identification of pyrazolodiazepinone, 22, which was >1000-fold selective for PDE2 over recombinant, full length PDEs 1B, 3A, 3B, 4A, 4B, 4C, 7A, 7B, 8A, 8B, 9, 10 and 11. Compound 22 also retained excellent PDE2 selectivity (241-fold to 419-fold) over the remaining recombinant, full length PDEs, 1A, 4D, 5, and 6. Compound 22 exhibited good pharmacokinetic properties and excellent oral bioavailability (F=78%, rat). In an in vivo rat model of OA pain, compound 22 had significant analgesic activity 1 and 3h after a single, 10 mg/kg, subcutaneous dose.

Topics: Analgesics; Animals; Azepines; Azirines; Binding Sites; Catalytic Domain; Crystallography, X-Ray; Cyclic Nucleotide Phosphodiesterases, Type 2; Dihydropyridines; Disease Models, Animal; Drug Evaluation, Preclinical; Half-Life; Osteoarthritis; Phosphodiesterase 4 Inhibitors; Phosphodiesterase Inhibitors; Protein Binding; Pyrazoles; Rats; Structure-Activity Relationship

2013