Pyrimido[4,5-d]azepines as potent and selective 5-HT2C receptor agonists: design, synthesis, and evaluation of PF-3246799 as a treatment for urinary incontinence.

New pyrimido[4,5-d]azepines 7 are disclosed as potent 5-HT(2C) receptor agonists. A preferred example, 7b had minimal activation at either the 5-HT(2A) or 5-HT(2B) receptors combined with robust efficacy in a preclinical canine model of stress urinary incontinence (SUI) and attractive pharmacokinetic and safety properties. Based on this profile, 7b (PF-3246799) was identified as a candidate for clinical development for the treatment of SUI. In addition, it proved to be critical to build an understanding of the translation between recombinant cell-based systems, native tissue preparations and in vivo preclinical models. This was a significant undertaking and proved to be crucial in compound selection.

Orally active and brain permeable proline amides as highly selective 5HT2c agonists for the treatment of obesity.

Brain-penetrable proline amides were developed as 5HT2c agonists with more than 1000-fold binding selectivity against 5HT2b receptor. After medicinal chemistry optimization and SAR studies, orally active proline amides with robust efficacy in a rodent food intake inhibition model were uncovered.

Leptin potentiates the anti-obesity effects of rimonabant.

We hypothesized that a combination of low doses of rimonabant and leptin would markedly reduce body weight through the modulation of neuronal activity within the hypothalamus. To this end, high fat diet-induced obese rats were randomized to receive either leptin (0.5mg/kg subcutaneously), rimonabant (3mg/kg), the combination of both, or vehicle, daily for a duration of 2 weeks. A subset of rats was pair-fed to the combination-treated animals and received either vehicle or leptin. At the end of the weight loss phase, leptin treatment was maintained for 7 days while rimonabant was discontinued to assess changes in body weight during the rebound phase. The combination of rimonabant and leptin resulted in a marked inhibition of food intake and a profound reduction in body weight that was greater than achieved with either leptin or rimonabant alone. Treatment with leptin during the rebound phase inhibited compensatory increases in body weight associated with restitution of ad libitum feeding in previously pair-fed rats. Moreover, leptin partially blunted the rebound in food intake and body weight associated with cessation of rimonabant therapy.To investigate the effect of the combination on neuronal firing in the rat hypothalamus, single unit activity was recorded from brain slices containing the ventromedial and arcuate nuclei. The combination of rimonabant and leptin synergistically increased and decreased neuronal firing in the ventromedial and arcuate nuclei, respectively. Overall, these data demonstrate profound anti-obesity effects of combining cannabinoid type 1 receptor antagonists and leptin.

Structure-activity relationships of triazolopyridine oxazole p38 inhibitors: identification of candidates for clinical development.

The synthesis, structure-activity relationship, in vivo activity, and metabolic profile for a series of triazolopyridine-oxazole based p38 inhibitors are described. The deficiencies of the lead structure in the series, CP-808844, were overcome by changes to the C4 aryl group and the triazole side-chain culminating in the identification of several potential clinical candidates.

Impaired inflammatory and pain responses in mice lacking an inducible prostaglandin E synthase.

Prostaglandin (PG)E2 is a potent mediator of pain and inflammation, and high levels of this lipid mediator are observed in numerous disease states. The inhibition of PGE2 production to control pain and to treat diseases such as rheumatoid arthritis to date has depended on nonsteroidal antiinflammatory agents such as aspirin. However, these agents inhibit the synthesis of all prostanoids. To produce biologically active PGE2, PGE synthases catalyze the isomerization of PGH2 into PGE2. Recently, several PGE synthases have been identified and cloned, but their role in inflammation is not clear. To study the physiological role of the individual PGE synthases, we have generated by targeted homologous recombination a mouse line deficient in microsomal PGE synthase 1 (mPGES1) on the inbred DBA/1lacJ background. mPGES1-deficient (mPGES1-/-) mice are viable and fertile and develop normally compared with wild-type controls. However, mPGES1-/- mice displayed a marked reduction in inflammatory responses compared with mPGES1+/+ mice in multiple assays. Here, we identify mPGES1 as the PGE synthase that contributes to the pathogenesis of collagen-induced arthritis, a disease model of human rheumatoid arthritis. We also show that mPGES1 is responsible for the production of PGE2 that mediates acute pain during an inflammatory response. These findings suggest that mPGES1 provides a target for the treatment of inflammatory diseases and pain associated with inflammatory states.