ABSTRACT
P2X3 receptor is an ATP-gated ion channel, mainly localized on peripheral sensory neurons. Currently, several clinical trials are being conducted with P2X3 receptor antagonists for the treatment of chronic pain or cough. To identify a P2X3 lead compound, we reexamined the HTS evaluation compounds and selected dioxotriazine derivatives from which we identified a hit compound. As a result of the hit-to-lead SAR, we obtained lead compound 1 which had a moderate inhibitory effect on P2X3 receptors (IC50, 128 nM). Further improvement of the potency and PK profiles of this lead compound finally led to the selected compound 74 (P2X3 IC50, 16.1 nM; P2X2/3 IC50, 2931 nM), which demonstrated a strong analgesic effect against allodynia on oral administration in the rat partial sciatic nerve ligation model of neuropathic pain (ED50, 3.1 mg/kg).
Subject(s)
Neuralgia/drug therapy , Purinergic P2X Receptor Antagonists/pharmacology , Receptors, Purinergic P2X3/metabolism , Triazines/pharmacology , Administration, Oral , Animals , Dose-Response Relationship, Drug , Humans , Microsomes, Liver/chemistry , Microsomes, Liver/metabolism , Molecular Structure , Neuralgia/metabolism , Purinergic P2X Receptor Antagonists/administration & dosage , Purinergic P2X Receptor Antagonists/chemistry , Rats , Structure-Activity Relationship , Triazines/administration & dosage , Triazines/chemistryABSTRACT
A novel series of (6-aminopyridin-3-yl)(4-(pyridin-2-yl)piperazin-1-yl) methanone derivatives were identified as selective transient receptor potential vanilloid 4 (TRPV4) channel antagonist and showed analgesic effect in Freund's Complete Adjuvant (FCA) induced mechanical hyperalgesia model in guinea pig and rat. Modification of right part based on the compound 16d which was disclosed in our previous communication led to the identification of compound 26i as a flagship compound. In this paper, we described the details about design, synthesis and structure-activity relationship (SAR) analysis at right and left part of these derivatives (Fig. 1).
Subject(s)
Analgesics/pharmacology , Azabicyclo Compounds/pharmacology , Pain Management/methods , TRPV Cation Channels/antagonists & inhibitors , Thiazoles/pharmacology , Analgesics/chemistry , Animals , Azabicyclo Compounds/chemistry , Guinea Pigs , Humans , Microsomes/drug effects , Proton Magnetic Resonance Spectroscopy , Rats , Spectrometry, Mass, Electrospray Ionization , Structure-Activity Relationship , Thiazoles/chemistryABSTRACT
A series of 2',4'-dimethyl-[4,5'-bithiazol]-2-yl amino derivatives have been identified as selective TRPV4 antagonists that display inhibition potencies against 4α-phorbol 12,13-didecanoate (4αPDD), well known as a TRPV4 selective agonist and/or a hypotonicity. In particular, 9-(6-((2',4'-dimethyl-[4,5'-bithiazol]-2-yl)amino)nicotinoyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-one showed an analgesic effect in Freund's Complete Adjuvant (FCA) induced mechanical hyperalgesia model in guinea pig (reported in Part 1). However, there are some concerns such as species differences and the need for higher plasma exposure to achieve target efficacy for evaluation by an in vivo pain model. In this Letter, we report the resolution of some of the problems by further optimizing the chemical scaffold.
