PDE5 inhibitors promote recovery of peripheral neuropathy in diabetic mice

Diabetes mellitus affects an estimated 422 million people worldwide.Peripheral neuropathy is one of the most common and disabling complications of diabetes.There is currently no effective treatment for diabetic neuropathy,

Influencing Factors for Erectile Dysfunction of Young Adults with No Response to PDE5i

Erectile dysfunction(ED)is a common male disorder.Although orally-administered phosphodiesterase type 5 inhibitors(PDE5 inhibitors)are now recognized as the primary pharmacological treatment method for ED,20%-30%of the patients treated with PDE5 inhibitors exhibit no significant effects.This study aims to investigate the influencing factors of ED in young adults with no response to PDE5 inhibitors.ED patients who would take PDE5 inhibitors were included and investigated with a questionnaire.Patients with no response to PDE5 inhibitors(tadalafil and sildenafil)served as study group,and those with response to PDE5 inhibitors as control group.Then Chi square test and logistic regression analysis were applied to find the potential influencing factors.In total,378 ED patients were included.Ninety-three(24.6%)cases were non-responsive to PDE5 inhibitors,and the remaining 285(75.4%)responded to PDE5 inhibitors.In multiple logistic regression analysis,we found that history of drinking(OR=3.152;95%CI 1.672-6.975),spousal noncooperation(OR=2.994;95%CI 1.589-5.638),number of fixed sex partners(OR=0.358;95%CI 0.132-0.651),duration of ED(OR=3.356;95%CI 1.352-8.333),and depression(OR=3.689;95%CI 1.579-8.979)could be the influencing factors for ED patients’non-response to PDE5 inhibitors.In conclusion,history of drinking,spousal noncooperation,number of fixed sex partner,long duration of ED,and depression could be the influencing factors for ED patients'non-response to PDE5 inhibitors.Patients and doctors should pay attention to these factors.

Design and Synthesis of Pyrido[1,2-e]purin-4(3H)-one Derivatives as Potential PDE 5 Inhibitors

A novel series of pyrido[ 1,2-e]purin-4（3H）-one derivatives containing polar substituents on 5＇-position were designed and prepared as potential PDE5 inhibitors. This paper reports the synthetic routes, 1H-NMR data, and the PDE5 inhibitory activities of the target compounds. The polar piperazinyl group contained （on 5＇-position） compound, 3B2, showed the highest activity among the tested derivatives but less potency than sildenafil 1.

The effects of long-term administration of tadalafil on STZ-induced diabetic rats with erectile dysfunction via a local antioxidative mechanism

Type 5 phosphodiesterase inhibitors （PDE51s） are well known being effective via the nitric oxide and cyclic guanosine monophosphate （NO-cGMP） pathway and are widely used in the treatment of diabetic erectile dysfunction （ED）. However, it is unclear whether other pathways may be involved in the treatment of diabetic ED with PDE51s. The purpose of this study was to clarify the role of antioxidants in diabetic ED treatment through the long-term administration of PDE51s. Three groups of Sprague-Dawley rats were utilized： Group N, the normal control; Group D, streptozotocin （STZ）-induced diabetic rats as a control; and Group D＋T, STZ-induced diabetic rats who received oral administration of tadalafil for 8 weeks. Erectile function was assessed by intracavernous pressure （ICP） and mean arterial pressure （MAP） during electrical stimulation of the cavernous nerve before euthanasia. The levels of malondialdehyde （MDA）, superoxide dismutase （SOD） and mitochondrial membrane potential （MMP） of cavernous tissue were assessed by biochemical analysis. The morphology of mitochondria was observed by electron microscopy. The ICP/MAP ratio was higher in Group D＋T than in Group D （P〈O.05）. The levels of MDA decreased and the activities of SOD increased in Group D＋T in comparison with Group D （P〈O.05）. The mitochondrial membrane potential level of cavernous tissue in diabetic rats was partially recovered by tadalafil treatment for 8 weeks. The morphology changes of mitochondria were also remarkably ameliorated in Group D＋T. Collectively, the long-term administration of tadalafil in diabetic rats partially reduced oxidative stress lesions of the penis via a local antioxidative stress pathway. Long-term dosages of tadalafil given once daily beginning soon after the onset of diabetes may aid in preventing rats from developing diabetic ED.

Synthesis and Evaluation of PDE5 Inhibitory Activity of Novel Pyrido[2＇,1＇：5,1]pyrazolo[4,3-d]pyrimidin-4-one Derivatives

Novel pyridopyrazolopyrimidinone derivatives were designed and synthesized as potential PDE5 inhibitors. The target compounds demonstrated significant inhibitory activity against human platelet PDE5, but less potent than sildenafil.

Free energy perturbation(FEP)-guided scaffold hopping

Scaffold hopping refers to computer-aided screening for active compounds with different structures against the same receptor to enrich privileged scaffolds,which is a topic of high interest in organic and medicinal chemistry.However,most approaches cannot efficiently predict the potency level of candidates after scaffold hopping.Herein,we identified potent PDE5 inhibitors with a novel scaffold via a free energy perturbation(FEP)-guided scaffold-hopping strategy,and FEP shows great advantages to precisely predict the theoretical binding potenciesΔGFEPbetween ligands and their target,which were more consistent with the experimental binding potenciesΔGEXP(the mean absolute deviations|ΔGFEP-ΔGEXP|<2 kcal/mol)than thoseΔGMM-PBSAorΔGMM-GBSApredicted by the MM-PBSA or MM-GBSA method.Lead L12 had an IC_(50) of 8.7 nmol/L and exhibited a different binding pattern in its crystal structure with PDE5 from the famous starting drug tadalafil.Our work provides the first report via the FEPguided scaffold hopping strategy for potent inhibitor discovery with a novel scaffold,implying that it will have a variety of future applications in rational molecular design and drug discovery.