Non-basic azolotriazinone MCHR1 antagonists for the treatment of obesity: An empirical brain-exposures-driven candidate selection for in vivo efficacy studies.

Non-basic azolotriazinones were explored using an empirical free brain exposures-driven approach to identify potent MCHR1 antagonists for evaluation in in vivo efficacy studies. An optimized lead from this series, 1j (rMCHR1 Ki=1.8 nM), demonstrated a 6.9% reduction in weight gain relative to vehicle in a rat model at 30 mg/kg after 4 days of once-daily oral treatment as a glycine prodrug. Despite a promising efficacy profile, an assessment of the biliary toxicity risk of this compound rendered this compound non-progressible.

Dihydropyrrolopyrazol-6-one MCHR1 antagonists for the treatment of obesity: Insights on in vivo efficacy from a novel FLIPR assay setup.

Our investigation of the structure-activity and structure-liability relationships for dihydropyrrolopyrazol-6-one MCHR1 antagonists revealed that off-rate characteristics, inferred from potencies in a FLIPR assay following a 2 h incubation, can impact in vivo efficacy. The in vitro and exposure profiles of dihydropyrrolopyrazol-6-ones 1b and 1e were comparable to that of the thienopyrimidinone counterparts 41 and 43 except for a much faster MCHR1 apparent off-rate. The greatly diminished dihydropyrrolopyrazol-6-one anti-obesity response may be the consequence of this rapid off-rate.

Glomerular autacoids stimulated by bradykinin regulate efferent arteriole tone.

BACKGROUND: We have shown that when efferent arterioles are perfused retrograde to avoid the influence of vasoactive autacoids released by the glomerulus, bradykinin causes dilatation via release of cytochrome p450 (cp450) metabolites, probably epoxyeicosatrienoic acids (EETs). Here we tested the hypothesis that the glomerulus releases cyclooxygenase (COX) and cp450 metabolites. These eicosanoids, acting as vasopressor and vasodepressor autacoids, control efferent arteriole resistance downstream from the glomerulus. METHODS: Rabbit efferent arterioles were perfused orthograde through the glomerulus from the end of the afferent arteriole to determine whether bradykinin induces the release of glomerular autacoids that influence efferent arteriole resistance. Efferent arterioles were preconstricted with norepinephrine, and increasing doses of bradykinin were added to the perfusate in the presence or absence of COX and cp450 inhibitors. RESULTS: When efferent arterioles were perfused orthograde through the glomerulus, bradykinin at 10 nmol/L caused significant and reproducible dilatation; diameter increased from 8.0 +/- 0.5 to 12.6 +/- 0.4 microm (P < 0.05). This effect was not modified by a nitric oxide synthase (NOS) inhibitor. In the presence of indomethacin, a COX inhibitor, bradykinin-induced dilatation was almost completely blocked (from 8.0 +/- 0.5 to 9.3 +/- 0.6 microm). This blockade was completely reversed by 20-hydroxyeicosa-6(Z),15(Z)-dienoic acid (20-HEDE), a specific antagonist of the vasoconstrictor cp450 metabolite 20-hydroxyeicosatetraenoic acid (20-HETE); diameter increased from 6.6 +/- 0.7 to 13.2 +/- 0.5 microm. To test the hypothesis that this dilatation was due to EETs, a specific inhibitor of EET synthesis, N-methylsulphonyl-6-(2-proparglyloxyphenyl)hexanamide (MS-PPOH), was added to the arteriolar perfusate. In the presence of indomethacin and 20-HEDE, bradykinin caused dilatation and this effect was completely blocked by MS-PPOH (1 microm) (from 7.6 +/- 0.6 to 7.3 +/- 0.5 microm). CONCLUSIONS: We concluded that in response to bradykinin, the glomerulus releases COX metabolites (probably prostaglandins) that have a vasodilator effect. When COXs are inhibited, the vasoconstrictor 20-HETE released by the glomerulus is able to oppose the vasodilator effect of bradykinin. This vasodilator effect is mediated by EETs released by the glomerulus and/or the efferent arteriole and does not involve nitric oxide. The balance between these opposing effects of various eicosanoids controls efferent arteriole resistance downstream from the glomerulus.