Discovery of a novel 2-(1H-pyrazolo[3,4-b]pyridin-1-yl)thiazole derivative as an EP1 receptor antagonist and in vivo studies in a bone fracture model

Masakazu Atobe; Kenji Naganuma; Masashi Kawanishi; Takahiko Hayashi; Hiroko Suzuki; Masahiro Nishida; Hirokazu Arai

doi:10.1016/j.bmcl.2018.06.022

Discovery of a novel 2-(1H-pyrazolo[3,4-b]pyridin-1-yl)thiazole derivative as an EP₁ receptor antagonist and in vivo studies in a bone fracture model

Bioorg Med Chem Lett. 2018 Aug 1;28(14):2408-2412. doi: 10.1016/j.bmcl.2018.06.022. Epub 2018 Jun 19.

Authors

Masakazu Atobe¹, Kenji Naganuma², Masashi Kawanishi², Takahiko Hayashi³, Hiroko Suzuki⁴, Masahiro Nishida³, Hirokazu Arai³

Affiliations

¹ Laboratory for Medicinal Chemistry, Asahi Kasei Pharma Corporation, 632-1 Mifuku, Izunokuni, Shizuoka 410-221, Japan. Electronic address: [email protected].
² Laboratory for Medicinal Chemistry, Asahi Kasei Pharma Corporation, 632-1 Mifuku, Izunokuni, Shizuoka 410-221, Japan.
³ Laboratory for Pharmacology, Asahi Kasei Pharma Corporation, 632-1 Mifuku, Izunokuni, Shizuoka 410-221, Japan.
⁴ Laboratory for Safety Assessment & ADME, Pharmaceutical Research Center, Asahi Kasei Pharma Corporation, 632-1 Mifuku, Izunokuni, Shizuoka 410-2321, Japan.

PMID: 29934246
DOI: 10.1016/j.bmcl.2018.06.022

Abstract

We describe a medicinal chemistry approach to the discovery of a novel EP₁ antagonist exhibiting high potency and good pharmacokinetics. Our starting point is 1, an EP₁ receptor antagonist that exhibits pharmacological efficacy in cystometry models following intravenous administration. Despite its good potency in vitro, the high lipophilicity of 1 is a concern in long-term in vivo studies. Further medicinal chemistry efforts identified 4 as an improved lead compound with good in vitro ADME profile applicable to long term in vivo studies. A rat fracture study was conducted with 4 for 4 weeks to validate its utility in bone fracture healing. The results suggest that this EP₁ receptor antagonist stimulates callus formation and thus 4 has potential for enhancing fracture healing.

Keywords: Bone fracture healing; EP(1) receptor; Oral administration; Prostaglandin E(2); Target validation.

MeSH terms

Animals
Disease Models, Animal
Dogs
Dose-Response Relationship, Drug
Drug Discovery*
Fracture Healing / drug effects*
Fractures, Bone / drug therapy*
Fractures, Bone / metabolism
Madin Darby Canine Kidney Cells / drug effects
Madin Darby Canine Kidney Cells / metabolism
Madin Darby Canine Kidney Cells / pathology
Mice
Mice, Knockout
Molecular Structure
Receptors, Prostaglandin E, EP1 Subtype / antagonists & inhibitors*
Receptors, Prostaglandin E, EP1 Subtype / deficiency
Receptors, Prostaglandin E, EP1 Subtype / metabolism
Structure-Activity Relationship
Thiazoles / chemistry
Thiazoles / pharmacology*

Substances

Receptors, Prostaglandin E, EP1 Subtype
Thiazoles