Tetrahydro-naphthols as orally available TRPV1 inhibitors.

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.

Naphthol derivatives as TRPV1 inhibitors for the treatment of urinary incontinence.

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.

Synthesis and optimization of novel and selective muscarinic M(3) receptor antagonists.

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.

Benzimidazole-5-sulfonamides as novel nonpeptide luteinizing hormone releasing hormone (LHRH) antagonists: minimization of mechanism-based CYP3A4 inhibition.

Herein we report the development of novel, potent and non-peptide luteinizing hormone releasing hormone (LHRH) antagonists. The optimization towards derivatives free from mechanism-based CYP3A4 inhibition is described. The identification of a main metabolite guided us towards structural modifications of the benzyl moiety, which resulted in significant improvements of the CYP3A4 profile, while maintaining potent LHRH antagonist activity.

Functional role of prostacyclin receptor in rat dorsal root ganglion neurons.

Recent studies on prostanoids showed that some of prostanoid receptors are expressed in rat dorsal root ganglion (DRG) neurons. These facts suggest that prostanoid receptors might be involved in the excitation mechanism of DRG neurons. In the present study, PCR experiments revealed that one of prostanoid receptor, prostacyclin receptor (IP receptor) was expressed in L6 and S1 rat DRG neurons and that the expression of IP receptor was not changed in DRG neurons obtained from the cyclophosphamide (CYP)-induced cystitis rat. We examined the functional role of IP receptor agonist and other prostanoids by measuring cyclic AMP (cAMP) accumulation and substance P (SP) release in primary cultured DRG neurons. The pretreatment of DRG neurons with prostanoid agonists such as iloprost (IP), butaprost (EP(2)), misoprostol (EP(2-4)), PGE(2) (EP(1-4)) or PGD(2) (DP and CRTH2) sensitized the DRG neurons and hence potentiated the lys-bradykinin-induced SP release. The increase of SP release by lys-BK plus prostanoid agonists was proportion to cAMP accumulation. Iloprost was the most potent agonist to induce cAMP accumulation and SP release among prostanoid agonists evaluated in this study and its effect is mediated by IP receptor. Moreover, capsaicin-, ATP- and KCl-induced SP release was also enhanced by iloprost although iloprost did not change intracellular Ca(2+) and membrane depolarization induced by these chemical stimuli. These results strongly indicate that IP receptor play an important role in the sensitization of rat sensory neuron.

Design, synthesis and activity of novel derivatives of oxybutynin and tolterodine.

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.

Benzimidazoles as non-peptide luteinizing hormone-releasing hormone (LHRH) antagonists. Part 3: Discovery of 1-(1H-benzimidazol-5-yl)-3-tert-butylurea derivatives.

1-(1H-Benzimidazol-5-yl)-3-tert-butylurea derivatives have been identified as a novel class of non-peptide luteinizing hormone-releasing hormone (LHRH) antagonists. Herein, we disclose the synthesis and structure-activity relationships (SAR) of this class resulting in the identification of compound 12c, with dual functional activity on human and rat receptors (rat LHRH: IC50=120 nM; human LHRH: IC50=18 nM). These SAR studies suggest that 1-(1H-benzimidazol-5-yl)-3-tert-butylurea is a new pharmacophore for small molecule LHRH antagonists.

Benzimidazole derivatives as novel nonpeptide luteinizing hormone-releasing hormone (LHRH) antagonists. Part 1: Benzimidazole-5-sulfonamides.

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.

Benzimidazole derivatives as novel nonpeptide luteinizing hormone-releasing hormone (LHRH) antagonists. Part 2: Benzimidazole-5-sulfonamides.

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).

Relaxant effect of oxygen free radicals on rabbit tracheal smooth muscle.

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.