Discovery of a pyrazolo[1,5-a]pyrimidine derivative (MT-3014) as a highly selective PDE10A inhibitor via core structure transformation from the stilbene moiety

Koizumi, Yuuki; Tanaka, Yoshihito; Matsumura, Takehiko; Kadoh, Yoichi; Miyoshi, Haruko; Hongu, Mitsuya; Takedomi, Kei; Kotera, Jun; Sasaki, Takashi; Taniguchi, Hiroyuki; Watanabe, Yumi; Takakuwa, Misae; Kojima, Kanako; Baba, Naomichi; Nakamura, Itsuko; Kawanishi, Eiji

doi:10.1016/j.bmc.2019.06.021

Cited by 9 publications

(5 citation statements)

References 29 publications

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“…Selective bromination of 3 with N-bromosuccinimide in dichloromethane afforded the bromo derivative 4 in 94% yield. The 3-bromo-7-(trifluoromethyl) pyrazolo [1,5-a]pyrimidin-5-one 4 served as a building block for the synthesis of 3,5-disubstituted 7-(trifluoromethyl)pyrazolo [1,5-a] a]pyrimidine derivatives were found to have an antiviral effect against the respiratory syncytial virus (RSV) [21] and hepatitis C virus [22], and are inhibitors of phosphodiesterase (PDE) 2A [23] and 10A [24][25][26], promising new targets for the treatment of cognitive disorders and schizophrenia, respectively. The incorporation of a fluorine atom into potential pharmaceutical substances has been successfully used as a key strategy for enhancing the activity of drugs or drug candidates [27,28].…”

Section: Resultsmentioning

confidence: 99%

“…Moreover, pyrazolo [1,5-a]pyrimidines are also known as antagonists of serotonin 5-HT6 receptors [15], and also act as inhibitors of histone lysine demethylase 4D (KDM4D) [16] as well as several kinases such as Pim kinase [17,18], threonine tyrosine kinase (TTK) [19], and cyclin-dependent kinases (CDKs) [20]. In addition, some pyrazolo [1,5-a]pyrimidine derivatives were found to have an antiviral effect against the respiratory syncytial virus (RSV) [21] and hepatitis C virus [22], and are inhibitors of phosphodiesterase (PDE) 2A [23] and 10A [24][25][26], promising new targets for the treatment of cognitive disorders and schizophrenia, respectively.…”

Section: Introductionmentioning

confidence: 99%

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Efficient Access to 3,5-Disubstituted 7-(Trifluoromethyl)pyrazolo[1,5-a]pyrimidines Involving SNAr and Suzuki Cross-Coupling Reactions

et al. 2020

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An efficient and original synthesis of various 3,5-disubstituted 7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidines is reported. A library of compounds diversely substituted in C-3 and C-5 positions was easily prepared from a common starting material, 3-bromo-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-5-one. In C-5 position, a SNAr type reaction was achieved by first activating the C–O bond of the lactam function with PyBroP (Bromotripyrrolidinophosphonium hexafluorophosphate), followed by the addition of amine or thiol giving monosubstituted derivatives, whereas in C-3 position, arylation was performed via Suzuki–Miyaura cross-coupling using the commercially available aromatic and heteroaromatic boronic acids. Moreover, trifluoromethylated analogues of potent Pim1 kinase inhibitors were designed following our concise synthetic methodology.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Efficient Access to 3,5-Disubstituted 7-(Trifluoromethyl)pyrazolo[1,5-a]pyrimidines Involving SNAr and Suzuki Cross-Coupling Reactions

et al. 2020

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“…The Ki value of MTP-X is 10 nM for PDE7 and 1.4 μM or higher for other PDEs. We also employed MT-3014 as a selective inhibitor of PDE10A [ 19 ].…”

Section: Methodsmentioning

confidence: 99%

“…These samples were then incubated for 60 min at room temperature in fresh buffer containing [ 11 C]MTP38 (2 nM) with or without unlabeled MTP38 (10 μM), MTP-X (4 μM), or MT-3014 (40 nM). The concentrations of MTP-X and MT-3014 were more than 400-fold of reported IC 50 values of these agents [ 19 ]. After the incubation, the brain sections were immersed twice in cold buffer for 3 min, dipped in cold distilled water for 10 s, and dried with warm airflow.…”

Section: Methodsmentioning

confidence: 99%

Synthesis and preclinical evaluation of [11C]MTP38 as a novel PET ligand for phosphodiesterase 7 in the brain

Obokata

Seki

Hirata

et al. 2021

Eur J Nucl Med Mol Imaging

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Purpose Phosphodiesterase (PDE) 7 is a potential therapeutic target for neurological and inflammatory diseases, although in vivo visualization of PDE7 has not been successful. In this study, we aimed to develop [11C]MTP38 as a novel positron emission tomography (PET) ligand for PDE7. Methods [11C]MTP38 was radiosynthesized by 11C-cyanation of a bromo precursor with [11C]HCN. PET scans of rat and rhesus monkey brains and in vitro autoradiography of brain sections derived from these species were conducted with [11C]MTP38. In monkeys, dynamic PET data were analyzed with an arterial input function to calculate the total distribution volume (VT). The non-displaceable binding potential (BPND) in the striatum was also determined by a reference tissue model with cerebellar reference. Finally, striatal occupancy of PDE7 by an inhibitor was calculated in monkeys according to changes in BPND. Results [11C]MTP38 was synthesized with radiochemical purity ≥99.4% and molar activity of 38.6 ± 12.6 GBq/μmol. Autoradiography revealed high radioactivity in the striatum and its reduction by non-radiolabeled ligands, in contrast with unaltered autoradiographic signals in other regions. In vivo PET after radioligand injection to rats and monkeys demonstrated that radioactivity was rapidly distributed to the brain and intensely accumulated in the striatum relative to the cerebellum. Correspondingly, estimated VT values in the monkey striatum and cerebellum were 3.59 and 2.69 mL/cm3, respectively. The cerebellar VT value was unchanged by pretreatment with unlabeled MTP38. Striatal BPND was reduced in a dose-dependent manner after pretreatment with MTP-X, a PDE7 inhibitor. Relationships between PDE7 occupancy by MTP-X and plasma MTP-X concentration could be described by Hill’s sigmoidal function. Conclusion We have provided the first successful preclinical demonstration of in vivo PDE7 imaging with a specific PET radioligand. [11C]MTP38 is a feasible radioligand for evaluating PDE7 in the brain and is currently being applied to a first-in-human PET study.

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“…138 PDEs are hydrolases that degrade intracellular signaling compounds vital to cellular functions such as cAMP and cGMP. Koizumi et al 139 have indicated the potency of quinoxalinyl-pyrrolidinyl-based pyrazolopyrimidine 227 as an inhibitor of PDE10A with high selectivity. Applying the rat CAR test, the compound was effective with positive symptoms of schizophrenia.…”

Section: Biological Characteristicsmentioning

confidence: 99%

Insights into the medicinal chemistry of heterocycles integrated with a pyrazolo[1,5-a]pyrimidine scaffold

2022

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Discovery of a pyrazolo[1,5-a]pyrimidine derivative (MT-3014) as a highly selective PDE10A inhibitor via core structure transformation from the stilbene moiety

Cited by 9 publications

References 29 publications

Efficient Access to 3,5-Disubstituted 7-(Trifluoromethyl)pyrazolo[1,5-a]pyrimidines Involving SNAr and Suzuki Cross-Coupling Reactions

Efficient Access to 3,5-Disubstituted 7-(Trifluoromethyl)pyrazolo[1,5-a]pyrimidines Involving SNAr and Suzuki Cross-Coupling Reactions

Synthesis and preclinical evaluation of [11C]MTP38 as a novel PET ligand for phosphodiesterase 7 in the brain

Insights into the medicinal chemistry of heterocycles integrated with a pyrazolo[1,5-a]pyrimidine scaffold

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