Delving into the Latest Updates on Takeda California, Inc. with Synapse

Overview

Intermolecular interactions between active pharmaceutical ingredients (APIs) and carrier polymers are important for the long-term physical stability of amorphous solid dispersions (ASDs). However, the negative impact of intermolecular interactions on chemical stability has rarely been reported. In this study, the relationship between intermolecular interactions and physical and chemical stability was investigated using two ASDs composed of API and hydroxypropyl methylcellulose acetate succinate (HPMCAS) with different stabilities: ASD1 was physically stable but chemically unstable, whereas ASD2 was physically unstable but chemically stable. Ionic-bonding between the pyridine nitrogen in the API and succinyl group in HPMCAS was found in both ASDs. The additional interaction between the succinyl group in HPMCAS and the hydroxyl group in the API was suggested only in ASD1. It was concluded that the additional interaction contributed to the physical stability of ASD1; however, it accelerated the chemical reaction between the succinyl and hydroxyl groups to generate succinyl ester owing to its close proximity. This study shows that the intermolecular interaction between the API and carrier polymer is not always beneficial for chemical stability. Understanding the molecular states of APIs and polymers in ASDs is important for their successful development.

01 Oct 2022·European Journal of Medicinal Chemistry

Design and synthesis of aryl-piperidine derivatives as potent and selective PET tracers for cholesterol 24-hydroxylase (CH24H)

Article

Author: Matsumiya, Kouta ; Kajita, Yuichi ; Ishii, Tsuyoshi ; Miyamoto, Maki ; Lane, Weston ; Kuroita, Takanobu ; Gay, Sean C ; Koike, Tatsuki ; Nishi, Toshiya ; Constantinescu, Cristian C ; Papin, Caroline ; Alagille, David ; Tamagnan, Gilles ; Ikeda, Shuhei

Cholesterol 24-hydroxylase (CH24H, CYP46A1) is a cytochrome P450 family enzyme that maintains the homeostasis of brain cholesterol. Soticlestat, a potent and selective CH24H inhibitor, is in development as a therapeutic agent for Dravet syndrome and Lennox-Gastaut syndrome. Herein, we report the discovery of aryl-piperidine derivatives as potent and selective CH24H positron emission tomography (PET) tracers which can be used for dose guidance of a clinical CH24H inhibitor and as a diagnostic tool for CH24H-related pathology. Starting from compound 1 (IC₅₀ = 16 nM, logD = 1.7), which was reported as a CH24H inhibitor with lower lipophilicity, a¹⁸F-labeling site (3-fluoroazetidine) was incorporated by structure-based drug design (SBDD) utilizing the co-crystal structure of a compound 1 analog. Subsequent optimization to adjust key parameters for PET tracers, such as potency, lipophilicity, brain penetration, and unbound plasma protein binding, enabled compounds 3f (IC₅₀ = 8.8 nM) and 3g (IC₅₀ = 8.7 nM) as PET imaging candidates. Selectivity of these compounds for CH24H was validated by a brain distribution study using CH24H-WT and KO mice. In non-human primate PET imaging, [¹⁸F]3f and [¹⁸F]3g showed similar regional uptake in the brain, indicating that these tracers were specific to the CH24H-expressed regions and validated the expression of CH24H in the living brain by different tracers.

01 Aug 2021·Nature Structural & Molecular Biology

Author Correction: Structures of the TRPM5 channel elucidate mechanisms of activation and inhibition

Author: Myers, Richard ; Lü, Wei ; Du, Juan ; Ruan, Zheng ; Haley, Emery ; Sabat, Mark ; Orozco, Ian J ; Roth, Rebecca

100 Deals associated with Takeda California, Inc.

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100 Translational Medicine associated with Takeda California, Inc.

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Pipeline

Pipeline Snapshot as of 23 Nov 2024

The statistics for drugs in the Pipeline is the current organization and its subsidiaries are counted as organizations,Early Phase 1 is incorporated into Phase 1, Phase 1/2 is incorporated into phase 2, and phase 2/3 is incorporated into phase 3

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