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phosphodiesterase 10a inhibitor PF-2545920 as a prospective agent for the clinical promotion of sperm motility

Asian Journal of Andrology 2023年第5期25卷 608-615页

作者： Yi-Ting Yang Bin Yan Yu-Hua Li Li-Na Guo Wei-Wei Wang Li-Jie Liu He-Guo Yu Hua Diao NHC Key Laboratory of Reproduction Regulation(Shanghai Institute for Biomedical and Pharmaceutical Technologies) School of Basic Medical SciencesFudan UniversityShanghai 200032China Reproductive Medicine Centre Zhongshan HospitalFudan UniversityShanghai 200032China School of Basic Medical Sciences Fudan UniversityShanghai 200032China Department of Urology Huashan HospitalFudan UniversityShanghai 200040China

phosphodiesterase(PDE)inhibitors can improve sperm motility in patients with ***,the most commonly reported nonselective PDE inhibitor pentoxifylline and PDE5 inhibitor sildenafil have the disadvantages of requiring a high concentration and destroying sperm *** examined the PDE10a inhibitor PF-2545920 to compare its ability to promote sperm motility with that of pentoxifylline and *** seminal plasma was discarded,several semen samples were subjected to four treatments(control,PF-2545920,pentoxifylline,and sildenafil)to evaluate their ability to affect motility,viability,and spontaneous acrosome *** calcium and adenosine triphosphate(ATP),mitochondrial membrane potential,and penetration through viscous medium were assessed by flow cytometry,luciferase,and hyaluronic acid after treatment with *** analyses were performed using the analysis of variance statistical ***-2545920 elevated the percentage of motile spermatozoa compared to the control,pentoxifylline,and sildenafil groups at 10μmol l^(-1)(P<0.01).It is less toxic to GC-2spd mouse spermatocytes cells and spermatozoa and causes fewer spontaneous acrosomal reactions(P<0.05).PF-2545920 also increased mitochondrial membrane potential(P<0.001)and altered intracellular calcium(P<0.05)in a dose-dependent manner,including increasing sperm hyaluronic acid penetrating ability(P<0.05).Therefore,PF-2545920 might be an excellent choiceforstimulatingthe spermmotility.

关键词： pentoxifylline phosphodiesterase 10a sildenafil sperm motility spontaneous acrosome reaction

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Discovery of a highly specific ^(18)F-labeled PET ligand for phosphodiesterase 10a enabled by novel spirocyclic iodonium ylide radiofluorination

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Acta Pharmaceutica Sinica B 2022年第4期12卷 1963-1975页

作者： Zhiwei Xiao Huiyi Wei Yi Xu Ahmed Haider Junjie Wei Shiyu Yuan Jian Rong Chunyu Zhao Guocong Li Weibin Zhang Huangcan Chen Yuefeng Li Lingling Zhang Jiyun Sun Shaojuan Zhang Hai-Bin Luo Sen Yan Qijun Cai Lu Hou Chao Che Steven H.Liang Lu Wang Center of Cyclotron and PET Radiopharmaceuticals Department of Nuclear Medicine and PET/CT-MRI Centerthe First Affiliated Hospital of Jinan UniversityGuangzhou 510630China Division of Nuclear Medicine and Molecular Imaging Massachusetts General Hospital&Department of RadiologyHarvard Medical SchoolBostonMA 02114USA Department of Cardiology the First Affiliated Hospital of Jinan UniversityGuangzhou 510630China State Key Laboratory of Chemical Oncogenomics Key Laboratory of Chemical GenomicsPeking University Shenzhen Graduate SchoolShenzhen 518055China Guangdong Landau Biotechnology Co.Ltd. Guangzhou 510555China Key Laboratory of Tropical Biological Resources of Ministry of Education School of Pharmaceutical SciencesHainan UniversityHaikou 570228China Guangdong-Hongkong-Macao Institute of CNS Regeneration Ministry of Education CNS Regeneration Collaborative Joint LaboratoryJinan UniversityGuangzhou 510632China

As a member of cyclic nucleotide phosphodiesterase(PDE)enzyme family,PDE10a is in charge of the degradation of cyclic adenosine(cAMP)and guanosine monophosphates(cGMP).While PDE10a is primarily expressed in the medium spiny neurons of the striatum,it has been implicated in a variety of neurological ***,inhibition of PDE10a has proven to be of potential use for the treatment of central nervous system(CNS)pathologies caused by dysfunction of the basal ganglia–of which the striatum constitutes the largest component.A PDE10a-targeted positron emission tomography(PET)radioligand would enable a better assessment of the pathophysiologic role of PDE10a,as well as confirm the relationship between target occupancy and administrated dose of a given drug candidate,thus accelerating the development of effective PDE10a *** this study,we designed and synthesized a novel ^(18)F-aryl PDE10a PET radioligand,codenamed[^(18)F]P10a-1910([^(18)F]9),in high radiochemical yield and molar activity via spirocyclic iodonium ylide-mediated radiofluorination.[^(18)F]9 possessed good in vitro binding affinity(IC_(50)=2.1 nmol/L)and selectivity towards ***,[^(18)F]9 exhibited reasonable lipophilicity(logD=3.50)and brain permeability(P_(app)>10×10^(−6) cm/s in MDCK-MDR1 cells).PET imaging studies of[^(18)F]9 revealed high striatal uptake and excellent in vivo specificity with reversible tracer *** studies in rodents revealed an improved plasma and brain stability of[^(18)F]9 when compared to the current reference standard for PDE10a-targeted PET,[^(18)F]***,dose–response experiments with a series of escalating doses of PDE10a inhibitor 1 in rhesus monkey brains confirmed the utility of[^(18)F]9 for evaluating target occupancy in vivo in higher *** conclusion,our results indicated that[^(18)F]9 is a promising PDE10a PET radioligand for clinical translation.

关键词： phosphodiesterase 10a PET radioligand 18F Spirocyclic iodonium ylide Nonhuman primate Target occupancy

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Discovery of highly selective and orally available benzimidazole-based phosphodiesterase 10 inhibitors with improved solubility and pharmacokinetic properties for treatment of pulmonary arterial hypertension

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Acta Pharmaceutica Sinica B 2020年第12期10卷 2339-2347页

作者： Yuncong Yangy Sirui Zhangy Qian Zhouy Chen Zhang Yuqi Gao Hao Wang Zhe Li Deyan Wu Yinuo Wu Yi-You Huang Lei Guo Hai-Bin Luo School of Pharmaceutical Sciences Sun Yat-sen UniversityGuangzhou 510006China

Optimization efforts were devoted to discover novel PDE10 A inhibitors in order to improve solubility and pharmacokinetics properties for a long-term therapy against pulmonary arterial hypertension(PAH)starting from the previously synthesized inhibitor *** a result,a potent and highly selective PDE10 A inhibitor,14·3 HC1(half maximal inhibitory concentration,IC50=2.8 nmol/L and>3500-fold selectivity)exhibiting desirable solubility and metabolic stability with a remarkable bioavailability of50%was identified with the aid of efficient methods of binding free energy *** PAH studies showed that the improvement offered by 14·3 HCl[2.5 mg/kg,oral administration(p.o.)]was comparable to tadalafil(5.0 mg/kg,p.o.),verifying the feasibility of PDE10 A inhibitors for the antiPAH *** crystal structure of the PDE10 A-14 complex illustrates their binding pattern,which provided a guideline for rational design of highly selective PDE10 A inhibitors.

关键词： phosphodiesterase 10a Inhibitor Benzimidazole derivatives Crystal structure Metabolic stability Bioavailability Pulmonary arterial hypertension

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