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

Y. Koizumi; Yoshihito Tanaka; Takehiko Matsumura; Yoichi Kadoh; Haruko Miyoshi; Mitsuya Hongu; Kei Takedomi; Jun Kotera; Takashi Sasaki; Hiroyuki Taniguchi; Yumi Watanabe; M. Takakuwa; Koki Kojima; Nobuyuki Baba; Itsuko Nakamura; Eiji Kawanishi

doi:10.1016/j.bmc.2019.06.021

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

Y. Koizumi, Yoshihito Tanaka, Takehiko Matsumura, Yoichi Kadoh, Haruko Miyoshi, Mitsuya Hongu, Kei Takedomi, Jun Kotera, Takashi Sasaki, Hiroyuki Taniguchi, Yumi Watanabe, M. Takakuwa, Koki Kojima, Nobuyuki Baba, Itsuko Nakamura, Eiji Kawanishi

Research output: Contribution to journal › Article › peer-review

9 Citations (Scopus)

Abstract

We have developed a new class of PDE10A inhibitor, a pyrazolo[1,5-a]pyrimidine derivative MT-3014 (1). A previous compound introduced was deprioritized due to concerns for E/Z-isomerization and glutathione-adduct formation at the core stilbene structure. We discovered pyrazolo [1,5-a] pyrimidine as a new lead scaffold by structure-based drug design utilizing a co-crystal structure with PDE10A. The lead compound was optimized for in vitro activity, solubility, and selectivity against human ether-á-go-go related gene cardiac channel binding. We observed that MT-3014 shows excellent efficacy in rat conditioned avoidance response test and suitable pharmacokinetic properties in rats, especially high brain penetration.

Original language	English
Pages (from-to)	3440-3450
Number of pages	11
Journal	Bioorganic and Medicinal Chemistry
Volume	27
Issue number	15
DOIs	https://doi.org/10.1016/j.bmc.2019.06.021
Publication status	Published - Aug 1 2019
Externally published	Yes

All Science Journal Classification (ASJC) codes

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

Access to Document

10.1016/j.bmc.2019.06.021

Cite this

Koizumi, Y., Tanaka, Y., Matsumura, T., Kadoh, Y., Miyoshi, H., Hongu, M., Takedomi, K., Kotera, J., Sasaki, T., Taniguchi, H., Watanabe, Y., Takakuwa, M., Kojima, K., Baba, N., Nakamura, I., & Kawanishi, E. (2019). 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. Bioorganic and Medicinal Chemistry, 27(15), 3440-3450. https://doi.org/10.1016/j.bmc.2019.06.021

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, Y.; Tanaka, Yoshihito; Matsumura, Takehiko et al.

In: Bioorganic and Medicinal Chemistry, Vol. 27, No. 15, 01.08.2019, p. 3440-3450.

Research output: Contribution to journal › Article › peer-review

Koizumi, Y, Tanaka, Y, Matsumura, T, Kadoh, Y, Miyoshi, H, Hongu, M, Takedomi, K, Kotera, J, Sasaki, T, Taniguchi, H, Watanabe, Y, Takakuwa, M, Kojima, K, Baba, N, Nakamura, I & Kawanishi, E 2019, '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', Bioorganic and Medicinal Chemistry, vol. 27, no. 15, pp. 3440-3450. https://doi.org/10.1016/j.bmc.2019.06.021

@article{29433117b07341549f7501cdb1db2202,

title = "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",

abstract = "We have developed a new class of PDE10A inhibitor, a pyrazolo[1,5-a]pyrimidine derivative MT-3014 (1). A previous compound introduced was deprioritized due to concerns for E/Z-isomerization and glutathione-adduct formation at the core stilbene structure. We discovered pyrazolo [1,5-a] pyrimidine as a new lead scaffold by structure-based drug design utilizing a co-crystal structure with PDE10A. The lead compound was optimized for in vitro activity, solubility, and selectivity against human ether-{\'a}-go-go related gene cardiac channel binding. We observed that MT-3014 shows excellent efficacy in rat conditioned avoidance response test and suitable pharmacokinetic properties in rats, especially high brain penetration.",

author = "Y. Koizumi and Yoshihito Tanaka and Takehiko Matsumura and Yoichi Kadoh and Haruko Miyoshi and Mitsuya Hongu and Kei Takedomi and Jun Kotera and Takashi Sasaki and Hiroyuki Taniguchi and Yumi Watanabe and M. Takakuwa and Koki Kojima and Nobuyuki Baba and Itsuko Nakamura and Eiji Kawanishi",

note = "Publisher Copyright: {\textcopyright} 2019 Elsevier Ltd",

year = "2019",

month = aug,

day = "1",

doi = "10.1016/j.bmc.2019.06.021",

language = "English",

volume = "27",

pages = "3440--3450",

journal = "Bioorganic and Medicinal Chemistry",

issn = "0968-0896",

publisher = "Elsevier Limited",

number = "15",

}

TY - JOUR

T1 - 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

AU - Koizumi, Y.

AU - Tanaka, Yoshihito

AU - Matsumura, Takehiko

AU - Kadoh, Yoichi

AU - Miyoshi, Haruko

AU - Hongu, Mitsuya

AU - Takedomi, Kei

AU - Kotera, Jun

AU - Sasaki, Takashi

AU - Taniguchi, Hiroyuki

AU - Watanabe, Yumi

AU - Takakuwa, M.

AU - Kojima, Koki

AU - Baba, Nobuyuki

AU - Nakamura, Itsuko

AU - Kawanishi, Eiji

PY - 2019/8/1

Y1 - 2019/8/1

N2 - We have developed a new class of PDE10A inhibitor, a pyrazolo[1,5-a]pyrimidine derivative MT-3014 (1). A previous compound introduced was deprioritized due to concerns for E/Z-isomerization and glutathione-adduct formation at the core stilbene structure. We discovered pyrazolo [1,5-a] pyrimidine as a new lead scaffold by structure-based drug design utilizing a co-crystal structure with PDE10A. The lead compound was optimized for in vitro activity, solubility, and selectivity against human ether-á-go-go related gene cardiac channel binding. We observed that MT-3014 shows excellent efficacy in rat conditioned avoidance response test and suitable pharmacokinetic properties in rats, especially high brain penetration.

AB - We have developed a new class of PDE10A inhibitor, a pyrazolo[1,5-a]pyrimidine derivative MT-3014 (1). A previous compound introduced was deprioritized due to concerns for E/Z-isomerization and glutathione-adduct formation at the core stilbene structure. We discovered pyrazolo [1,5-a] pyrimidine as a new lead scaffold by structure-based drug design utilizing a co-crystal structure with PDE10A. The lead compound was optimized for in vitro activity, solubility, and selectivity against human ether-á-go-go related gene cardiac channel binding. We observed that MT-3014 shows excellent efficacy in rat conditioned avoidance response test and suitable pharmacokinetic properties in rats, especially high brain penetration.

UR - http://www.scopus.com/inward/record.url?scp=85067580984&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85067580984&partnerID=8YFLogxK

U2 - 10.1016/j.bmc.2019.06.021

DO - 10.1016/j.bmc.2019.06.021

M3 - Article

C2 - 31235264

AN - SCOPUS:85067580984

SN - 0968-0896

VL - 27

SP - 3440

EP - 3450

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

IS - 15

ER -

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

Abstract

All Science Journal Classification (ASJC) codes

Access to Document

Other files and links

Fingerprint

Cite this