862270-47-1

Upstream product

• 42137-88-2 N,N-bis(2-chloroethyl)-p-toluenesulfonamide 
• 374898-01-8 (R)-1-(4-fluorophenyl)ethylamine 

Downstream Products

• 862270-48-2 (R)-4-[1-(4-fluorophenyl)ethyl]piperazine 

Relevant academic research and scientific papers

Practical synthesis of a vanilloid receptor-1 antagonist

(Chemical Equation Presented) Small molecule TRPV1 antagonists have been a recent focus in the search for pain treatment agents. We herein describe a practical and scalable synthesis of AMG 628 (1), a bis-substituted pyrimidine derivative that was identif

Novel vanilloid receptor-1 antagonists: 3. The identification of a second-generation clinical candidate with improved physicochemical and pharmacokinetic properties

Based on the previously reported clinical candidate, AMG 517 (compound 1), a series of related piperazinylpyrimidine analogues were synthesized and evaluated as antagonists of the vanilloid 1 receptor (VR1 or TRPV1). Optimization of in vitro potency and physicochemical and pharmacokinetic properties led to the discovery of (R)-N-(4-(6-(4-(1-(4-fluorophenyl)ethyl) piperazin-1-yl)pyrimidin-4-yloxy)benzo[d]-thiazol-2-yl)acetamide (16p), a potent TRPV1 antagonist [rTRPV1(CAP) IC50 = 3.7 nM] with excellent aqueous solubility (≥200 μg/mL in 0.01 N HCl) and a reduced half-life (rat t 1/2 = 3.8 h, dog t1/2 = 2.7 h, monkey t1/2 = 3.2 h) as compared to AMG 517. In addition, compound 16p was shown to be efficacious at blocking a TRPV1-mediated physiological response in vivo (ED 50 = 1.9 mg/kg, p.o. in the capsaicin-induced flinch model in rats) and was also effective at reducing thermal hyperalgesia induced by complete Freund's adjuvant in rats (MED = 1 mg/kg, p.o). Based on its improved overall profile, compound 16p (AMG 628) was selected as a second-generation candidate for further evaluation in human clinical trials as a potential new treatment for chronic pain.

VANILLOID RECEPTOR LIGANDS AND THEIR USE IN TREATMENTS

Pyrimidine ethers and compositions containing them, for the treatment of acute, inflammatory and neuropathic pain, dental pain, general headache, migraine, cluster headache, mixed-vascular and non-vascular syndromes, tension headache, general inflammation, arthritis, rheumatic diseases, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, chronic inflammatory conditions, inflammatory pain and associated hyperalgesia and allodynia, neuropathic pain and associated hyperalgesia and allodynia, diabetic neuropathy pain, causalgia, sympathetically maintained pain, deafferentation syndromes, asthma, epithelial tissue damage or dysfunction, herpes simplex, disturbances of visceral motility at respiratory, genitourinary, gastrointestinal or vascular regions, wounds, burns, allergic skin reactions, pruritus, vitiligo, general gastrointestinal disorders, gastric ulceration, duodenal ulcers, diarrhea, gastric lesions induced by necrotising agents, hair growth, vasomotor or allergic rhinitis, bronchial disorders or bladder disorders.

Vanilloid receptor ligands and their use in treatments

Compounds having the general structure and compositions containing them, for the treatment of acute, inflammatory and neuropathic pain, dental pain, general headache, migraine, cluster headache, mixed-vascular and non-vascular syndromes, tension headache,