78686-84-7

Upstream product

• 29241-62-1 5-bromo-6-chloronicotinic acid 
• 41668-13-7 5-bromo-6-hydroxy-3-pyridinecarboxylic acid 
• 29241-64-3 5,6-Dibromnicotinsaeure 

Downstream Products

• 78686-77-8 5-bromo-6-chloro-3-pyridinecarboxylic acid methyl ester 

Relevant academic research and scientific papers

Disposition of asciminib, a potent BCR-ABL1 tyrosine kinase inhibitor, in healthy male subjects

Asciminib is a potent, specific BCR-ABL1 inhibitor being developed for the treatment of patients with chronic myelogenous leukemia (CML) and Philadelphia chromosome positive acute lymphoblastic leukemia (Ph + ALL). Here, we present the results of human oral absorption, distribution, metabolism, excretion (ADME) and in vitro studies that together provide an overall understanding of the metabolism, distribution and clearance of asciminib in humans. Asciminib was rapidly absorbed with a maximum plasma concentration at two hours post-dose. Total radioactivity and asciminib showed similar terminal half-lives in plasma. Oral asciminib absorption ranged between a minimum of 33%, and a maximum of 57% based on the metabolite profiles of late time-point feces collections. Asciminib was eliminated mainly through feces via unchanged asciminib excretion and metabolism. Direct glucuronidation and oxidation were major metabolic pathways in human that were catalyzed predominantly by UDP-glucuronosyltransferase (UGT)2B7 and cytochrome P450 (CYP)3A4, respectively. The relative contribution of the glucuronidation pathway to the total clearance of asciminib via metabolism is estimated to range ～28–58%, whereas the relative contribution of the oxidative pathway is estimated to range ～37–64%, based upon the maximum oral absorption in humans.

Scaffold hopping enables direct access to more potent PROTACs with: In vivo activity

Herein we employ a scaffold hopping approach to enhance the activity of a previously reported BCR-Abl PROTAC. This represents a significant advance in the PROTAC field since it can abrogate the need to optimize the linker to access a more potent degrader.

Discovery of Asciminib (ABL001), an Allosteric Inhibitor of the Tyrosine Kinase Activity of BCR-ABL1

Chronic myelogenous leukemia (CML) arises from the constitutive activity of the BCR-ABL1 oncoprotein. Tyrosine kinase inhibitors (TKIs) that target the ATP-binding site have transformed CML into a chronic manageable disease. However, some patients develop drug resistance due to ATP-site mutations impeding drug binding. We describe the discovery of asciminib (ABL001), the first allosteric BCR-ABL1 inhibitor to reach the clinic. Asciminib binds to the myristate pocket of BCR-ABL1 and maintains activity against TKI-resistant ATP-site mutations. Although resistance can emerge due to myristate-site mutations, these are sensitive to ATP-competitive inhibitors so that combinations of asciminib with ATP-competitive TKIs suppress the emergence of resistance. Fragment-based screening using NMR and X-ray yielded ligands for the myristate pocket. An NMR-based conformational assay guided the transformation of these inactive ligands into ABL1 inhibitors. Further structure-based optimization for potency, physicochemical, pharmacokinetic, and drug-like properties, culminated in asciminib, which is currently undergoing clinical studies in CML patients.

OXADIAZOLE MODULATORS OF S1P METHODS OF MAKING AND USING

The invention is directed to Compounds of Formula (I): wherein each variable is defined herein, as well as methods of making and using the compounds as agonists of S1P1 and/or S1P5 for instance for treating graft versus host disease and autoimmune diseases.

THIADIAZOLE MODULATORS OF S1P AND METHODS OF MAKING AND USING

The invention is directed to compounds of the formula: wherein each of the variables are defined herein, as well as methods of making and using the compounds as agonists of S1P1 and/or S1P5 for instance treating an autoimmune disease.

Small molecule disruptors of the glucokinase-glucokinase regulatory protein interaction: 4. Exploration of a novel binding pocket

Structure-activity relationship investigations conducted at the 5-position of the N-pyridine ring of a series of N-arylsulfonyl-N′-2-pyridinyl- piperazines led to the identification of a novel bis-pyridinyl piperazine sulfonamide (51) that was a potent disruptor of the glucokinase-glucokinase regulatory protein (GK-GKRP) interaction. Analysis of the X-ray cocrystal of compound 51 bound to hGKRP revealed that the 3-pyridine ring moiety occupied a previously unexplored binding pocket within the protein. Key features of this new binding mode included forming favorable contacts with the top face of the Ala27-Val28-Pro29 ("shelf region") as well as an edge-to-face interaction with the Tyr24 side chain. Compound 51 was potent in both biochemical and cellular assays (IC50 = 0.005 μM and EC 50 = 0.205 μM, respectively) and exhibited acceptable pharmacokinetic properties for in vivo evaluation. When administered to db/db mice (100 mg/kg, po), compound 51 demonstrated a robust pharmacodynamic effect and significantly reduced blood glucose levels up to 6 h postdose.

COMPOUNDS AND COMPOSITIONS FOR INHIBITING THE ACTIVITY OF ABL1, ABL2 AND BCR-ABL1

The present invention relates to compounds of formula I: in which Y, Y1, Y 4, Y5, Y 6, R1, R2, R3 and R4 are defined in the Summary of the Invention; capable of inhibiting the activity of BCR-ABL1 and mutants thereof. The invention further provides a process for the preparation of compounds of the invention, pharmaceutical preparations comprising such compounds and methods of using such compounds in the treatment of cancers.

PYRIDYL AND PHENYL SUBSTITUTED PIPERAZINE-PIPERIDINES WITH CXCR3 ANTAGONIST ACTIVITY

The present application discloses a compound, or enantiomers, stereoisomers, rotamers, tautomers, racemates or prodrug of said compound, or pharmaceutically acceptable salts, solvates or esters of said compound, or of said prodrug, said compound having the general structure shown in Formula 1: and the pharmaceutically acceptable salts, solvates and esters thereof. Also disclosed is a method of treating chemokine mediated diseases, such as, palliative therapy, curative therapy, prophylactic therapy of certain diseases and conditions such as inflammatory diseases (non limiting example(s) include, psoriasis), autoimmune diseases (non limiting example(s) include, rheumatoid arthritis, multiple sclerosis), graft rejection (non limiting example(s) include, allograft rejection, xenograft rejection), infectious diseases (e.g , tuberculoid leprosy), fixed drug eruptions, cutaneous delayed-type hypersensitivity responses, ophthalmic inflammation, type I diabetes, viral meningitis and tumors using a compound of Formula 1.

Some Methyl 2,5- and 5,6-Dihalonicotinates

The preparation of the methyl esters of eight dihalonicotinic acids is described.The esters were synthesized either by the methanolysis of their respective acid chlorides or by treatment of the appropriate acid with diazomethane in ether.Experimental and spectral data for the methyl dihalonicotinates are presented.