Delving into the Latest Updates on I-022 with Synapse

Targeting CDK4/6 has been identified as an effective therapeutics for treatment of cancer. We herein reported the discovery of a series of 6-(2-(methylamino)ethyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine derivatives as CDK4/6 inhibitors against cancer. Compound 3c, which displayed high potency and selectivity on CDK4/6 (IC₅₀ = 0.710/1.10 nM) over a variety of other kinases, possessed desirable antiproliferative activities, excellent metabolic properties, and favorable pharmacokinetic characters. In MCF-7, Colo-205, and A549 xenograft models, compound 3c exhibited significant tumor growth inhibitions with low toxicities, which could be a promising drug candidate for further development.

28 Mar 2019·Journal of Medicinal ChemistryQ1 · MEDICINE

Discovery of N-(4-[¹⁸F]Fluoro-5-methylpyridin-2-yl)isoquinolin-6-amine (JNJ-64326067), a New Promising Tau Positron Emission Tomography Imaging Tracer

Q1 · MEDICINE

Article

Author: Leenaerts, Joseph E. ; te Riele, Paula ; Xia, Chunfang A. ; Iturrino, Laura ; Song, Fengbin ; Vandenberghe, Rik ; Kolb, Hartmuth ; Rombouts, Frederik J. R. ; Andres, Jose-Ignacio ; Bormans, Guy ; Wuyts, Stijn ; Bottelbergs, Astrid ; Declercq, Lieven ; Wintmolders, Cindy ; Moechars, Diederik ; Chen, Lu ; Marien, Jonas

In Alzheimer's disease, the density and spread of aggregated tau protein track well with neurodegeneration and cognitive decline, making the imaging of aggregated tau a compelling biomarker. A structure-activity relationship exploration around an isoquinoline hit, followed by an exploration of tolerated fluorination positions, allowed us to identify 9 (JNJ-64326067), a potent and selective binder to aggregated tau with a favorable pharmacokinetic profile and no apparent off-target binding. This was confirmed in rat and monkey positron emission tomography studies using [¹⁸F]9.

01 Apr 2001·European Journal of PharmacologyQ3 · MEDICINE

A61603-induced vasoconstriction in porcine carotid vasculature: involvement of a non-adrenergic mechanism

Q3 · MEDICINE

Article

Author: Beril Tom ; Kapil Kapoor ; Jan P.C Heiligers ; Peter De Vries ; Edwin W Willems ; Carlos M Villalón ; Pramod R Saxena

It has recently been shown that the pharmacological profile of alpha(1)-adrenoceptors mediating constriction of porcine carotid arteriovenous anastomoses resembles that of alpha(1A)- and alpha(1B)-adrenoceptor subtypes. In an attempt to verify the involvement of alpha(1A)-adrenoceptors, we used the potent alpha(1A)-adrenoceptor agonist N-[5-(4,5-dihydro-1H-imidazol-2yl)-2-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl]methane sulphonamide (A61603) and found that intracarotid (i.c.) administration of A61603 (0.3-10 microg kg(-1)) dose-dependently decreased porcine carotid blood flow and vascular conductance. This decrease was exclusively due to a constriction of carotid arteriovenous anastomoses; the capillary blood flow and conductance remained unchanged. Surprisingly, the responses to A61603 were little modified by prior i.v. treatment with 5-methylurapidil (1000 microg kg(-1)), prazosin (100 microg kg(-1)) or a combination of prazosin and rauwolscine (100 and 300 microg kg(-1), respectively). The 5-HT(1B/1D) receptor antagonist N-[4-methoxy-3-(4-methyl-1-piperazinyl) phenyl]-2'-methyl-4'(5-methyl-1,2,4-oxadiazol-3-yl)[1,1,-biphenyl]-4-carboxamide hydrochloride monohydrate (GR127935; 500 microg kg(-1)) and ketanserin (500 microg kg(-1)) also failed to modify carotid vascular responses to A61603, but, interestingly, methiothepin (3000 microg kg(-1)) proved to be an effective antagonist. Taken together, the present results show that A61603 is a relatively poor agonist at the alpha(1A)-adrenoceptor in anaesthetised pigs and that the carotid vasoconstriction produced by A61603 is mediated by a novel non-adrenergic mechanism.

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Indication	Highest Phase	Country/Location	Organization	Date
Locally advanced breast cancer	Phase 3	China	Shanghai Pharmaceuticals Holding Co., Ltd.	08 Sep 2023
Advanced Liposarcoma	Phase 2	China	Shanghai Pharmaceuticals Holding Co., Ltd.	17 Oct 2023
Brain metastases	Phase 2	China	Shanghai Pharmaceuticals Holding Co., Ltd.	19 Sep 2023
Advanced Malignant Solid Neoplasm	Phase 2	China	Shanghai Pharmaceuticals Holding Co., Ltd.	03 Nov 2020
Liposarcoma	Phase 2	United States	Shanghai Pharmaceuticals Holding Co., Ltd.	-
Solid tumor	Phase 2	United States	Shanghai Pharmaceuticals Holding Co., Ltd.	-
PIK3CA mutation/HR-positive/HER2-negative Breast Cancer	Preclinical	China	Shanghai Pharmaceuticals Holding Co., Ltd.	19 Sep 2023
Dedifferentiated Liposarcoma	Preclinical	United States	Shanghai Pharma Biotherapeutics Usa, Inc.	31 Aug 2023
Hormone receptor positive HER2 negative breast cancer	Preclinical	China	Shanghai Pharmaceuticals Holding Co., Ltd.	24 Apr 2023
Metastatic breast cancer	Preclinical	China	Shanghai Pharmaceuticals Holding Co., Ltd.	24 Apr 2023