859516-82-8

Upstream product

• 13331-27-6 m-nitrobenzene boronic acid 
• 859516-81-7 2-chloro-4-(3-nitrophenyl)pyrimidine 
• 883199-27-7 N-[3-(2-chloropyrimidin-4-yl)-phenyl]-carbamic acid 1,1-dimethylethyl ester 

Downstream Products

• 1354567-47-7 but-3-enoic acid [3-(2-{3-[(allylmethylamino)methyl]phenylamino}pyrimidin-4-yl)phenyl]amide 
• 1354566-63-4 but-3-enoic acid [3-(2-chloropyrimidin-4-yl)phenyl]amide 
• 1026029-12-8 C₁₆H₁₃ClN₄ 
• 883199-29-9 3-{[3-[2-(3-chlorophenylamino)-pyrimidin-4-yl]-phenyl]-amino}-3-oxopropanoic acid methyl ester 

Relevant academic research and scientific papers

Structural Optimization of the Diarylurea PSNCBAM-1, an Allosteric Modulator of Cannabinoid Receptor 1

Background: Structure–activity relationship studies improve the pharmacological and pharmacokinetic properties of a lead compound such as PSNCBAM-1, an allosteric modulator of the cannabinoid receptor 1. Objectives: Here, several derivatives of PSNCBAM-1 were synthesized with the aim of reducing the number of rings within its structure and enhancing the solubility of the compounds. The derivatives studied contain substituents previously shown to enhance binding of agonists (ie, a cyano group and a pyrimidine ring), with a reduced number of rings compared with the parent compound, PSNCBAM-1. Methods: The synthesized compounds were tested for the enhancement of the binding of orthosteric cannabinoid receptor 1 agonist CP55,940 in the presence of varying concentrations of each test compound. Select compounds were also tested for their effects on cannabinoid receptor 1 inverse agonist SR141716A binding. The compounds were also subjected to computational analysis of drug-like properties and solubility. Results: Consistent with a positive allosteric modulator for orthosteric ligand binding, compounds LDK1317 (12a), LDK1320 (12b), LDK1321 (6a), LDK1323 (8a), and LDK1324 (6b) all enhanced the binding of agonist CP55,940 to some degree. Reduction in the number of rings did not abolish the activity. The new lead compounds LDK1317 (12a) and LDK1321 (6a) showed improved drug-like properties and enhanced solubility in silico. Conclusions: In contrast to PSNCBAM-1, the synthesized compounds are analogs with fewer rings. The compounds LDK1317 (12a) and LDK1321 (6a) contained only 2 or 3 rings, respectively, and showed the binding parameters (KB = 110 nM, α = 2.3, and KB = 85 nM, α = 5.9). Further, the computationally predicted drug-like properties and solubility suggest these compounds are acceptable new lead compounds for further development of cannabinoid receptor 1 allosteric modulators. (Curr Ther Res Clin Exp. 2020; 81:XXX–XXX)

Pyrimidinyl Biphenylureas: Identification of New Lead Compounds as Allosteric Modulators of the Cannabinoid Receptor CB1

The allosteric modulator 1-(4-chlorophenyl)-3-(3-(6-(pyrrolidin-1-yl)pyridin-2-yl)phenyl)urea (PSNCBAM-1, 2) bound the cannabinoid receptor 1 (CB1) and antagonized G protein coupling. This compound demonstrated potent anorectic effects similar to the CB1 antagonist rimonabant that once was marketed for the treatment of obesity, suggesting a new chemical entity for the discovery of antiobesity drugs. To increase structural diversity of this class of CB1 ligands, we designed and synthesized two classes of novel analogues, in which the pyridine ring of 2 was replaced by a pyrimidine ring. These positively modulate the binding of the CB1 orthosteric agonist CP55,940 while exhibiting an antagonism of G-protein coupling activity. Interestingly, compounds 7d and 8d demonstrated ERK1/2 phosphorylation mediated via β-arrestin unlike the orthosteric CP55,940 that does so in a G protein-dependent manner. These can serve as new lead compounds for the future development of CB1 allosteric modulators that show biased agonism and potentially antiobesity behavior via a new mechanism.

Discovery of kinase spectrum selective macrocycle (16E)-14-methyl-20-oxa-5, 7,14,26-tetraazatetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8(27) ,9,11,16,21,23-decaene (SB1317/TG02), a potent inhibitor of cyclin dependent kinases (CDKs), Janus kinase 2 (JAK2), and Fms-like tyrosine kinase-3 (FLT3) for the treatment of cancer

Herein, we describe the design, synthesis, and SAR of a series of unique small molecule macrocycles that show spectrum selective kinase inhibition of CDKs, JAK2, and FLT3. The most promising leads were assessed in vitro for their inhibition of cancer cell proliferation, solubility, CYP450 inhibition, and microsomal stability. This screening cascade revealed 26h as a preferred compound with target IC50 of 13, 73, and 56 nM for CDK2, JAK2 and FLT3, respectively. Pharmacokinetic (PK) studies of 26h in preclinical species showed good oral exposures. Oral efficacy was observed in colon (HCT-116) and lymphoma (Ramos) xenograft studies, in line with the observed PK/PD correlation. 26h (SB1317/TG02) was progressed into development in 2010 and is currently undergoing phase 1 clinical trials in advanced leukemias and multiple myeloma.

Synthesis of analogs of the phenylamino-pyrimidine type protein kinase C inhibitor CGP 60474 utilizing a Negishi cross-coupling strategy

Analogs of 3-{4-[2-(3-chlorophenylamino)-pyrimidin-4-yl]-pyridin-2-yl- amino}-propanol (CGP 60474) were synthesized as useful models for the evaluation of structure-activity relationships of phenylamino-pyrimidine-type protein kinase C inhibitors. The app

2-(AMINO-SUBSTITUTED)-4-ARYL PYRAMIDINES AND RELATED COMPOUNDS USEFUL FOR TREATING INFLAMMATORY DISEASES

A heterocyclic inhibitor having the formula (I), with the variables defined herein, which is useful for treating inflammatory and other physiological disorders in which PKC-theta isoform plays a role.