Delving into the Latest Updates on R-932348 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

5-Fluoro-N-(4-methyl-3-propionylaminosulfonylphenyl)-N'-(4-(prop-2-ynyloxy)phenyl)-2,4-pyrimidinediamine

+ [2]

Target

JAK3 x Syk

Mechanism

JAK3 inhibitors(Tyrosine-protein kinase JAK3 inhibitors), Syk inhibitors(Spleen tyrosine kinase inhibitors)

Therapeutic Areas

Immune System DiseasesEye DiseasesOther Diseases+ [1]

Active Indication-

Inactive Indication

Chronic graft-versus-host diseaseGraft RejectionKerato conjunctivitis sicca+ [3]

Originator Organization

Rigel Pharmaceuticals, Inc.

Active Organization-

Inactive Organization

Rigel Pharmaceuticals, Inc.

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

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Structure

Molecular FormulaC28H35FN6O5S

InChIKeyLZMBOMHVTNXZSS-UHFFFAOYSA-M

CAS Registry1620142-65-5

View All Structures (2)

As the continuous rise in the incidence of antibiotic resistance, it is urgent to develop novel chemical scaffolds with antibacterial activities to control the spread of resistance to conventional antibiotics. In this study, a series of phenylthiazole and phenylthiophene pyrimidindiamine derivatives were designed and synthesized by modifying the hit compound (N²-isobutyl-N⁴-((4-methyl-2-phenylthiazol-5-yl)methyl) pyrimidine-2,4-diamine) and their antibacterial activities were evaluated both in vitro and in vivo. Among the tested compounds, compound 14g (N⁴-((5-(3-bromophenyl)thiophen-2-yl)methyl)-N²-isobutylpyrimidine-2,4-diamine) displayed the best antibacterial activities, which was not only capable of inhibiting E. coli and S. aureus growth at concentrations as low as 2 and 3 μg/mL in vitro, but also efficacious in a mice model of bacteremia in vivo. Unlike conventional antibiotics, compound 14g was elucidated to mainly destroy the bacterial cell membrane, with the dissipation of membrane potential and leakage of contents, ultimately leading to cell death. The destruction of cell structure is challenging to induce bacterial resistance, which suggested that compound 14g may be a kind of promising alternatives to antibiotics against bacteria.

23 Jan 2020·Journal of Medicinal ChemistryQ1 · MEDICINE

Synthesis and Biological Evaluation of B-Cell Lymphoma 6 Inhibitors of N-Phenyl-4-pyrimidinamine Derivatives Bearing Potent Activities against Tumor Growth

Q1 · MEDICINE

Article

Author: Huang, Dongxia ; Xing, Yajing ; Zhang, Qiansen ; Pang, Xiufeng ; Xu, Shifen ; Zhou, Miaoran ; Gu, Haijun ; Chen, Yihua ; He, Peng ; Xie, Jiuqing ; Guo, Weikai ; Yi, Zhengfang ; Liu, Mingyao

The transcriptional repressor B-cell lymphoma 6 (BCL6) is frequently misregulated in diffuse large B-cell lymphoma (DLBCL) and has emerged as an attractive drug target for the treatments of lymphoma. In this article, a series of N-phenyl-4-pyrimidinamine derivatives were designed and synthesized as potent BCL6 inhibitors by optimizing hit compound N⁴-(3-chloro-4-methoxyphenyl)-N²-isobutyl-5-fluoro-2,4-pyrimidinediamine on the basis of the structure-activity relationship. Among them, compound 14j displayed the most potent activities, which significantly blocked the interaction of BCL6 with its corepressors, reactivated BCL6 target genes in a dose-dependent manner, and had better effects compared with the two positive controls. Further studies indicated that a low dose of 14j could effectively inhibit germinal center formation. More importantly, 14j not only showed potent inhibition of DLBCL cell proliferation in vitro but also strongly suppressed the growth of DLBCL in vivo.

01 Nov 2018·Pakistan journal of pharmaceutical sciences

Synthesis, in vitro and in silico studies of S-alkylated 5-(4-methoxyphenyl)-4-phenyl-4H-1,2,4-triazole-3-thiols as cholinesterase inhibitors.

Article

Author: Saleem, Rahman Shah Zaib ; Siddiqui, Sabahat Zahra ; Rehman, Azizur ; Rehman, Jameel ; Khalid, Hira ; Hussain, Rashid ; Abbasi, Muhammad Athar ; Khan, Uzman ; Ashraf, Muhammad ; Arfan, Muhammad ; Shah, Syed Adnan Ali

The research was aimed to unravel the enzymatic potential of sequentially transformed new triazoles by chemically converting 4-methoxybenzoic acid via Fischer's esterification to 4-methoxybenzoate which underwent hydrazinolysis and the corresponding hydrazide (1) was cyclized with phenyl isothiocyanate (2) via 2-(4-methoxybenzoyl)-N-phenylhydrazinecarbothioamide (3); an intermediate to 5-(4-methoxyphenyl)-4-phenyl-4H-1,2,4-triazol-3-thiol (4). The electrophiles; alkyl halides 5(a-g) were further reacted with nucleophilic S-atom to attain a series of S-alkylated 5-(4-methoxyphenyl)-4-phenyl-4H-1,2,4-triazole-3-thiols 6(a-g). Characterization of synthesized compounds was accomplished by contemporary spectral techniques such as FT-IR, 1H-NMR, 13C-NMR and EI-MS. Excellent cholinesterase inhibitory potential was portrayed by 3-(n-heptylthio)-5-(4-methoxyphenyl)-4-phenyl-4H-1,2,4-triazole; 6g against AChE (IC50; 38.35±0.62μM) and BChE (IC50; 147.75±0.67μM) enzymes. Eserine (IC50; 0.04±0.01μM) was used as reference standard. Anti-proliferative activity results ascertained that derivative encompassing long straight chain substituted at S-atom of the moiety was the most potent with 4.96 % cell viability (6g) at 25μM and with 2.41% cell viability at 50μMamong library of synthesized derivatives. In silico analysis also substantiated the bioactivity statistics.

100 Deals associated with R-932348

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External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB06321

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Chronic graft-versus-host disease	Phase 2	US	Rigel Pharmaceuticals, Inc.	01 Mar 2014
Kerato conjunctivitis sicca	Phase 2	US	Rigel Pharmaceuticals, Inc.	01 Jul 2013
Graft Rejection	Phase 2	US	Rigel Pharmaceuticals, Inc.	-
Psoriasis	Phase 2	US	Rigel Pharmaceuticals, Inc.	-
Rheumatoid Arthritis	Phase 2	US	Rigel Pharmaceuticals, Inc.	-
Xerophthalmia	Phase 2	-	Rigel Pharmaceuticals, Inc.	-

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02040623 (DROPS-2, CTgov)	Phase 2	Chronic graft-versus-host disease \| Kerato conjunctivitis sicca	35	R348 Ophthalmic Solution, 0.2% (R348 Ophthalmic Solution, 0.2%)	jyelfljuiq(vorsuhnpex) = hscehgwyeg lineomytrs (jhqcdfvjuq, skjdqeivma - amwxuxmyqa) View more	-	10 Oct 2016
				R348 Ophthalmic Solution, 0.5% (R348 Ophthalmic Solution, 0.5%)	jyelfljuiq(vorsuhnpex) = haxawchafx lineomytrs (jhqcdfvjuq, nfsieirzbr - ynfdzdxqms) View more
NCT01900249 (DROPS, CTgov)	Phase 2	Kerato conjunctivitis sicca	204	R348 Ophthalmic Solution, 0.2% (R348 Ophthalmic Solution, 0.2%)	kxeslynota(vvwiokfpxd) = dkyhcrbyyj eeoahqciyy (sstzsjivzf, qccwwzhulr - tvbjxytvrr) View more	-	03 Oct 2016
				R348 Ophthalmic Solution, 0.5% (R348 Ophthalmic Solution, 0.5%)	kxeslynota(vvwiokfpxd) = lkkmbblael eeoahqciyy (sstzsjivzf, tjrbfhbnmp - rueehcweuu) View more