ABSTRACT
N-type calcium channels (Ca(v)2.2) have been shown to play a critical role in pain. A series of low molecular weight 2-aryl indoles were identified as potent Ca(v)2.2 blockers with good in vitro and in vivo potency.
Subject(s)
Calcium Channel Blockers/therapeutic use , Calcium Channels, N-Type/metabolism , Indoles/therapeutic use , Pain/drug therapy , Animals , Calcium Channel Blockers/pharmacokinetics , Calcium Channel Blockers/pharmacology , Dogs , Haplorhini , Humans , Indoles/pharmacokinetics , Indoles/pharmacology , RatsABSTRACT
A series of novel biphenyl pyrazole dicarboxamides were identified as potential sodium channel blockers for treatment of neuropathic pain. Compound 20 had outstanding efficacy in the Chung rat spinal nerve ligation (SNL) model of neuropathic pain.
Subject(s)
Biphenyl Compounds/chemistry , Neuralgia/drug therapy , Pyrazoles/chemistry , Sodium Channel Blockers/chemistry , Sodium Channels/chemistry , Animals , Biphenyl Compounds/chemical synthesis , Biphenyl Compounds/therapeutic use , Dogs , Drug Evaluation, Preclinical , Humans , Mice , Microsomes, Liver/metabolism , Motor Activity/drug effects , Pyrazoles/pharmacokinetics , Pyrazoles/therapeutic use , Rats , Sodium Channel Blockers/pharmacokinetics , Sodium Channel Blockers/therapeutic use , Sodium Channels/metabolismABSTRACT
Voltage-gated sodium channels have been shown to play a critical role in neuropathic pain. A series of low molecular weight biaryl substituted pyrazole carboxamides were identified with good in-vitro potency and in-vivo efficacy. Compound 26, a Nav1.7 blocker has excellent efficacy in the Chung model of neuropathic pain.
Subject(s)
Neuralgia/drug therapy , Pyrazoles/chemistry , Pyrazoles/therapeutic use , Sodium Channel Blockers/chemistry , Sodium Channel Blockers/therapeutic use , Sodium Channels/metabolism , Animals , Dogs , Haplorhini , Humans , Microsomes, Liver/metabolism , NAV1.7 Voltage-Gated Sodium Channel , Pyrazoles/pharmacokinetics , Pyrazoles/pharmacology , Rats , Sodium Channel Blockers/pharmacokinetics , Sodium Channel Blockers/pharmacology , Structure-Activity RelationshipABSTRACT
Voltage-gated sodium channels have been shown to play a critical role in neuropathic pain. With a goal to develop potent peripherally active sodium channel blockers, a series of low molecular weight biaryl substituted imidazoles, oxazoles, and thiazole carboxamides were identified with good in vitro and in vivo potency.
Subject(s)
Neuralgia/drug therapy , Oxazoles/therapeutic use , Sodium Channel Blockers/therapeutic use , Sodium Channels/metabolism , Thiazoles/therapeutic use , Animals , Dogs , Humans , Imidazoles/chemistry , Imidazoles/metabolism , Imidazoles/pharmacology , Imidazoles/therapeutic use , Microsomes, Liver/metabolism , NAV1.7 Voltage-Gated Sodium Channel , Oxazoles/chemistry , Oxazoles/metabolism , Oxazoles/pharmacology , Rats , Sodium Channel Blockers/chemistry , Sodium Channel Blockers/metabolism , Sodium Channel Blockers/pharmacology , Thiazoles/chemistry , Thiazoles/metabolism , Thiazoles/pharmacologySubject(s)
Antineoplastic Agents, Alkylating/chemical synthesis , Dioxoles/chemical synthesis , Tetrahydroisoquinolines/chemical synthesis , Antineoplastic Agents, Alkylating/chemistry , Catalysis , Dioxoles/chemistry , Molecular Structure , Stereoisomerism , Tetrahydroisoquinolines/chemistry , TrabectedinABSTRACT
We report the enantioselective total synthesis of cribrostatin IV (1). Key features of this synthesis involve the convergent coupling of two highly functionalized homochiral components followed by a "lynchpin" Mannich cyclization to establish the pentacyclic core (cf. 19 --> 20).
Subject(s)
Isoquinolines/chemical synthesis , Amides/chemical synthesis , Amides/chemistry , Animals , Porifera/chemistryABSTRACT
[reaction: see text] In model studies directed to the total synthesis of Et743, a strategic S-C bond formation in systems 26 and 27 was demonstrated. It was further shown that Pictet-Spengler cyclization leading to spiro product 33 exhibits very high stereoselection.
Subject(s)
Antineoplastic Agents, Alkylating/chemical synthesis , Dioxoles/chemical synthesis , Isoquinolines/chemical synthesis , Spiro Compounds/chemical synthesis , Urochordata/chemistry , Animals , Indicators and Reagents , Lactones , Molecular Conformation , Stereoisomerism , Tetrahydroisoquinolines , TrabectedinABSTRACT
An "sp2 -sp3 Stille coupling" of the vinyl triflate 1 and the stannyl compound 2 is a key step toward the completion of the total synthesis of eleutherobin, a natural product exhibiting taxol-like cytotoxic activity.
