ABSTRACT
Starting from a naphthol-based lead series with low oral bioavailability, we have identified potent TRPV1 antagonists with oral bioavailability in rats. These compounds emerged from SAR studies aimed at replacing the lead's phenol structure whilst maintaining potency. Compound rac-6a is an orally available TRPV1 antagonist with single-digit nanomolar activity. The enantiomers show a low eudismic ratio at the receptor level.
Subject(s)
Naphthols/pharmacology , TRPV Cation Channels/antagonists & inhibitors , Administration, Oral , Animals , Biological Availability , Naphthols/administration & dosage , Naphthols/pharmacokinetics , Rats , Rats, Sprague-DawleyABSTRACT
We have identified naphthol derivatives as inhibitors of the vanilloid receptor TRPV1 by high throughput screening. The initial lead showed high clearance in rats and has been optimized by enhancing the acidity of the phenol group. Compound 6b has reduced clearance, improved potency and is active in rat cystometry models of urinary incontinence after intravenous administration.
Subject(s)
Naphthols/chemistry , TRPV Cation Channels/antagonists & inhibitors , Urinary Incontinence/drug therapy , Animals , Disease Models, Animal , Female , Inhibitory Concentration 50 , Molecular Structure , Naphthols/chemical synthesis , Naphthols/therapeutic use , Parenteral Nutrition , Rats , Structure-Activity RelationshipABSTRACT
A series of constrained piperidine analogues were synthesized as novel muscarinic M(3) receptor antagonists. Evaluation of these compounds in binding assays revealed that they not only have high affinity for the M(3) receptor but also have high selectivity over the M(2) receptor.
Subject(s)
Muscarinic Antagonists/chemical synthesis , Muscarinic Antagonists/pharmacology , Receptor, Muscarinic M3/antagonists & inhibitors , Muscarinic Antagonists/chemistry , Structure-Activity RelationshipABSTRACT
Novel derivatives of Tolterodine (1) and Oxybutynin (2) have been designed using conformationally restricted azabicyclics as replacement for open-chain amines. The synthesis and structure-activity relationships are presented.
Subject(s)
Benzhydryl Compounds/chemical synthesis , Benzhydryl Compounds/pharmacology , Cresols/chemical synthesis , Cresols/pharmacology , Drug Design , Mandelic Acids/chemical synthesis , Mandelic Acids/pharmacology , Phenylpropanolamine/chemical synthesis , Phenylpropanolamine/pharmacology , Animals , Benzhydryl Compounds/metabolism , Binding Sites/drug effects , Cresols/metabolism , Mandelic Acids/metabolism , Phenylpropanolamine/metabolism , Rats , Receptor, Muscarinic M2/metabolism , Receptor, Muscarinic M3/metabolism , Structure-Activity Relationship , Tolterodine TartrateABSTRACT
A new class of benzimidazole-5-sulfonamides has been identified as nonpeptide luteinizing hormone-releasing hormone (LHRH) antagonists. Initial structure-activity relationships are presented resulting in compounds 19 and 28 with submicromolar dual functional activity on human and rat receptors.
Subject(s)
Benzimidazoles/chemical synthesis , Benzimidazoles/pharmacology , Gonadotropin-Releasing Hormone/antagonists & inhibitors , Animals , Humans , Inhibitory Concentration 50 , Ligands , Rats , Structure-Activity RelationshipABSTRACT
The 2-cyclopropyl substituted benzimidazole 2 has been used as a starting point for further optimization of an LHRH antagonist series. SAR studies revealed that a tert-butyl urea fragment connected through a simple carbon chain would improve activity. Further modification of the benzylsulfonamide moiety led to the discovery of 23 (IC(50): 4.2 nM).
Subject(s)
Benzimidazoles/chemical synthesis , Benzimidazoles/pharmacology , Gonadotropin-Releasing Hormone/antagonists & inhibitors , Humans , Inhibitory Concentration 50 , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/pharmacology , UreaABSTRACT
We investigated the effect of exogenously generated superoxide anions (O(2)(-)), hydrogen peroxide (H(2)O(2)) and hydroxyl radicals (.OH) on isolated rabbit tracheal smooth muscle suspended in Krebs-Ringer solution. The ability of oxygen free radicals (OFRs) to affect acetyicholine (Ach)-induced contraction in these muscles was also investigated. OFRs, in general, produced a concentration-dependent relaxation of the tracheal smooth muscle in the doses used. However, in large concentrations, O(2)(-) and H(2)O(2) produced effects which were smaller than those obtained with lower concentrations. The relaxant effects of these oxyradicals were progressive and lasted throughout the 20min observation period. At all concentrations used, the OFRs tended to abolish or reduce Ach-induced contraction in a concentration-dependent manner. O(2)(-) was more potent than H(2)O(2) or DHF in relaxing the Ach-precontracted muscle and in inhibiting the response of the muscle to Ach. OFR-induced relaxation of the Ach-contracted muscle was not due to inactivation of the Ach by OFRs. Relaxation produced by OFRs was greater in preparations with intact epithelium than in those denuded of epithelium. The relaxant effects were blocked by indomethacin, a cyclooxygenase inhibitor. OFRs in the presence of indomethacin produced contraction only in the preparations with intact epithelium, suggesting a release of contractile factor(s) from epithelium. These results suggest that OFRs relax rabbit tracheal smooth muscle. The relaxation appears to be mediated through the synthesis and release of prostaglandins from the epithelium and smooth muscles.
