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

Plummer, Mark S.; Cornicelli, Joseph A.; Roark, Howard; Skalitzky, Donald J.; Stankovic, Charles J.; Bove, Susan E.; Pandit, J.; Goodman, Annise; Hicks, J. Kevin; Shahripour, Aurash; Beidler, David; Lu, Xiao Kang; Sanchez, Brian; Whitehead, Christopher; Sarver, Ron; Braden, Timothy; Gowan, Richard; Shen, Xuehui; Welch, Katherine; Ogden, Adam; Sadagopan, Nalini; Baum, Heidi; Miller, Howard L.; Banotai, Craig; Spessard, Cindy; Lightle, Sandra

doi:10.1016/j.bmcl.2013.03.082

Cited by 16 publications

(8 citation statements)

References 9 publications

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“…The details of the 32 pyrazolodiazepinone compounds for the present study were taken from the literature [9,10]. These molecules have been reported as inhibitors of PDE2.…”

Section: Materials and Methods 21 Datasetsmentioning

confidence: 99%

“…The recently reported crystal structure of PDE2 inhibitor complex was obtained from the Protein Data Bank (PDB: 4JIB) [9,10]. Since the structure is a tetramer with duplicate binding sites, extra binding sites and the associated chains were removed by picking and deleting molecules or chains and only the 'D' chain was kept for the docking study.…”

Section: Dockingmentioning

confidence: 99%

“…Pfizer's chemical database divulged a series of phosphodiesterase 4 (PDE4) diazepinone inhibitors which often had low levels of PDE2 inhibition [8]. Extensive structure-activity relationship (SAR) studies of these diazepinone inhibitors showed selective potency towards PDE2 inhibition [9,10].…”

Section: Introductionmentioning

confidence: 99%

“…A series of novel pyrazolodiazepinone derivatives with potent and selective inhibition activity toward PDE2 have been reported [9,10]. In order to derive a correlation between the structure and biological activity of these inhibitors, we have carried out a three-dimensional quantitative structure-activity relationship (3D-QSAR) study using comparative molecular field analysis (CoMFA) [11], comparative molecular similarity indices analysis (CoMSIA) [12], Topomer CoMFA [13] and a two-dimensional QSAR (2D-QSAR) study using Hologram QSAR (HQSAR) methods [14].…”

Section: Introductionmentioning

confidence: 99%

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Combined 2D and 3D-QSAR, molecular modelling and docking studies of pyrazolodiazepinones as novel phosphodiesterase 2 inhibitors

Bhansali

Kulkarni

2014

SAR and QSAR in Environmental Research

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Selective inhibition of phosphodiesterase 2 (PDE2) in cells where it is located elevates cyclic guanosine monophosphate (cGMP) and acts as novel analgesic with antinociceptive activity. Three-dimensional quantitative structure-activity relationship (QSAR) studies for pyrazolodiazepinone inhibitors exhibiting PDE2 inhibition were performed using comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA) and Topomer CoMFA, and two-dimensional QSAR study was performed using a Hologram QSAR (HQSAR) method. QSAR models were generated using training set of 23 compounds and were validated using test set of nine compounds. The optimum partial least squares (PLS) for CoMFA-Focusing, CoMSIA-SDH, Topomer CoMFA and HQSAR models exhibited good 'leave-one-out' cross validated correlation coefficient (q(2)) of 0.790, 0.769, 0.840 and 0.787, coefficient of determination (r(2)) of 0.999, 0.964, 0.979 and 0.980, and high predictive power (r(2)(pred)) of 0.796, 0.833, 0.820 and 0.803 respectively. Docking studies revealed that those inhibitors able to bind to amino acid Gln859 by cGMP binding orientation called 'glutamine-switch', and also bind to the hydrophobic clamp of PDE2 isoform, could possess high selectivity for PDE2. From the results of all the studies, structure-activity relationships and structural requirements for binding to active site of PDE2 were established which provide useful guidance for the design and future synthesis of potent PDE2 inhibitors.

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“…The details of the 32 pyrazolodiazepinone compounds for the present study were taken from the literature [9,10]. These molecules have been reported as inhibitors of PDE2.…”

Section: Materials and Methods 21 Datasetsmentioning

confidence: 99%

Section: Dockingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Combined 2D and 3D-QSAR, molecular modelling and docking studies of pyrazolodiazepinones as novel phosphodiesterase 2 inhibitors

Bhansali

Kulkarni

2014

SAR and QSAR in Environmental Research

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“…У працях [37][38][39] зреалізовано метод синтезу піразолодіазепінів 54, який включає використан-ня естерів 4-нітропіразоло-3-карбонових кислот 55. Їх селективне N-1-алкілування за Міцунобу при-водить до похідних 56, гідролізом яких отриму-ють кислоти 57, які конденсацією з гідрохлори-дом амінокетону переводять у аміди 58.…”

Section: піразоло[43-e][14]діазепін-8-ониunclassified

2-amino-5-(4-chloro-1h-imidazol-5-yl)-1,3,4-thiadiazoles: synthesis, pyrimidoannulation and the bactericidal activity

Grozav¹,

Chornous²,

Gavrylyuk³

et al. 2013

J. org. pharm. chem.

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2 ТОВ «НВП «Єнамін» 3 НТУУ «Київський політехнічний інститут ім. Ігоря Сікорського» Азоло[1,4]діазепіни: методи синтезу та структурна модифікаціяУзагальнені та систематизовані літературні джерела, які стосуються методів синтезу та хімічних перетво-рень відомих на теперішній час азоло [1,4]діазепінів: піразоло-, імідазо-, триазоло-, ізоксазоло-, оксазоло-, ізотіазоло-та тіазолодіазепінів. Значна увага приділена піразоло [1,4]діазепінам як найбільш досліджено-му типу азолодіазепінових систем. Відзначена їх роль як важливих субстанцій для дизайну сполук із по-тужним фармакологічним потенціалом. Детально розглянуті методи синтезу піразоло [3,4-e]

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The State of the Art in Selective PDE2A Inhibitor Design

Ende

Kormos

Humphrey

2014

Phosphodiesterases and Their Inhibitors

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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

Cited by 16 publications

References 9 publications

Combined 2D and 3D-QSAR, molecular modelling and docking studies of pyrazolodiazepinones as novel phosphodiesterase 2 inhibitors

Combined 2D and 3D-QSAR, molecular modelling and docking studies of pyrazolodiazepinones as novel phosphodiesterase 2 inhibitors

2-amino-5-(4-chloro-1h-imidazol-5-yl)-1,3,4-thiadiazoles: synthesis, pyrimidoannulation and the bactericidal activity

The State of the Art in Selective PDE2A Inhibitor Design

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