ABSTRACT
In a series of bradykinin B1 antagonists, we discovered that replacement of oxopiperazine acetamides with dehydro-oxopiperazine acetamides provided compounds with enhanced activity against the B1 receptor. The synthesis and SAR leading to potent analogs with reduced molecular weight will be discussed.
Subject(s)
Acetamides/pharmacology , Bradykinin B1 Receptor Antagonists , Piperazines/pharmacology , Acetamides/chemical synthesis , Acetamides/chemistry , Dose-Response Relationship, Drug , Humans , Molecular Structure , Piperazines/chemical synthesis , Piperazines/chemistry , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The discovery of novel and highly potent oxopiperazine based B1 receptor antagonists is described. Compared to the previously described arylsulfonylated (R)-3-amino-3-phenylpropionic acid series, the current compounds showed improved in vitro potency and metabolic stability. Compound 17, 2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(1-piperidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide, showed EC(50) of 10.3 nM in a rabbit biochemical challenge model. The practical syntheses of chiral arylsulfonylated oxopiperazine acetic acids are also described.
Subject(s)
Acetamides/therapeutic use , Bradykinin B1 Receptor Antagonists , Inflammation/drug therapy , Pain/drug therapy , Piperazines/therapeutic use , Acetamides/chemical synthesis , Acetamides/chemistry , Animals , Dogs , Inhibitory Concentration 50 , Mice , Models, Animal , Molecular Structure , Piperazines/chemical synthesis , Piperazines/chemistry , Rabbits , Rats , Receptor, Bradykinin B1/chemistry , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Recent years have seen the rapid advancement of new therapeutic agents against hepatitis C virus (HCV) in response to the need for treatment that is unmet by interferon (IFN)-based therapies. Most antiviral drugs discovered to date are small molecules that modulate viral enzyme activities. In the search for highly selective protein-binding molecules capable of disrupting the viral life cycle, we have identified a class of anionic tetraphenylporphyrins as potent and specific inhibitors of the HCV replicons. Based on the structure-activity relationship studies reported herein, meso-tetrakis-(3,5-dicarboxy-4,4'-biphenyl) porphyrin was found to be the most potent inhibitor of HCV genotype 1b (Con1) replicon systems but was less effective against the genotype 2a (JFH-1) replicon. This compound induced a reduction of viral RNA and protein levels when acting in the low nanomolar range. Moreover, the compound could suppress replicon rebound in drug-treated cells and exhibited additive to synergistic effects when combined with protease inhibitor BILN 2061 or with IFN-alpha-2a. Our results demonstrate the potential use of tetracarboxyphenylporphyrins as potent anti-HCV agents.
Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Hepacivirus/drug effects , Hepacivirus/genetics , Mesoporphyrins/chemistry , Mesoporphyrins/pharmacology , Carbamates/pharmacology , Cell Line , DNA, Mitochondrial/drug effects , DNA, Mitochondrial/genetics , Dose-Response Relationship, Drug , Drug Discovery , Drug Resistance, Viral , Drug Synergism , Genotype , Humans , Interferon alpha-2 , Interferon-alpha/pharmacology , Macrocyclic Compounds/pharmacology , Quinolines/pharmacology , RNA, Viral/drug effects , RNA, Viral/genetics , Recombinant Proteins , Replicon , Structure-Activity Relationship , Thiazoles/pharmacology , Viral Nonstructural Proteins/drug effects , Viral Nonstructural Proteins/geneticsABSTRACT
We report the development of aryl sulfones as Bradykinin B1 receptor antagonists. Variation of the linker region identified diol 23 as a potent B1 antagonist, while modifications of the aryl moiety led to compound 26, both of which were efficacious in rabbit biochemical challenge and pain models.
Subject(s)
Bradykinin B1 Receptor Antagonists , Pain/drug therapy , Sulfones/pharmacology , Animals , Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Bradykinin B2 Receptor Antagonists , Chronic Disease , Humans , Rabbits , Rats , Rats, Sprague-Dawley , Sulfones/administration & dosageABSTRACT
A family of tetrabiphenylporphyrin-based receptors has been synthesized. Receptor 7 showed sub-nanomolar affinity (K(d)=0.67 nM) in binding to the surface of cytochrome c. In addition, a stoichiometric amount of the receptor 7 caused a lowering in the T(m) of cytochrome c from 85 to 35 degrees C.
