1400633-26-2Relevant academic research and scientific papers
Discovery of trisubstituted pyrazolines as a novel scaffold for the development of selective phosphodiesterase 5 inhibitors
Abdel-Halim, Mohammad,Tinsley, Heather,Keeton, Adam B.,Weam, Mohammed,Atta, Noha H.,Hammam, Mennatallah A.,Hefnawy, Amr,Hartmann, Rolf W.,Engel, Matthias,Piazza, Gary A.,Abadi, Ashraf H.
, (2020/10/12)
Celecoxib, is a selective cyclooxygenase-2 (COX2) inhibitor with a 1,5-diaryl pyrazole scaffold. Celecoxib has a better safety profile compared to other COX2 inhibitors having side effects of systemic hypertension and thromboembolic complications. This may be partly attributed to an off-target activity involving phosphodiesterase 5 (PDE5) inhibition and the potentiation of NO/cGMP signalling allowing coronary vasodilation and aortic relaxation. Inspired by the structure of celecoxib, we synthesized a chemically diverse series of compounds containing a 1,3,5-trisubstituted pyrazoline scaffold to improve PDE5 inhibitory potency, while eliminating COX2 inhibitory activity. SAR studies for PDE5 inhibition revealed an essential role for a carboxylic acid functionality at the 1-phenyl and the importance of the non-planar pyrazoline core over the planar pyrazole with the 5-phenyl moiety tolerating a range of substituents. These modifications led to new PDE5 inhibitors with approximately 20-fold improved potency to inhibit PDE5 and no COX-2 inhibitory activity compared with celecoxib. PDE isozyme profiling of compound 11 revealed a favorable selectivity profile. These results suggest that trisubstituted pyrazolines provide a promising scaffold for further chemical optimization to identify novel PDE5 inhibitors with potential for less side effects compared with available PDE5 inhibitors used for the treatment of penile erectile dysfunction and pulmonary hypertension.
DERIVATIVES OF CELECOXIB, USE THEREOF AND PREPARATION THEREOF
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Page/Page column 19, (2012/10/07)
Derivatives of celecoxib that lack cyclooxygenase inhibitory activity but have improved PDE5 inhibitory activity are provided along with pharmaceutical compositions containing them for the treatment or prevention of cancer. Such compounds are expected to have reduced toxicity compared with celecoxib and other cyclooxygenase inhibitors, and greater efficacy compared with conventional PDE5 inhibitors. Derivatives of celecoxib are also suitable for treating chronic inflammatory conditions, erectile dysfunction, pulmonary hypertension, congestive heart failure, and enhancement of cognitive function.
