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[4-(4-Methyl-2-(4-(trifluoromethyl)phenyl)thiazole-5-yl)pyrimidine-2-amine] (JNJ-2482272), under investigation as an anti-inflammatory agent, was orally administered to rats once daily at 60 mg/kg for 6 consecutive days. Despite high plasma exposure after single administration (Cmax of 7.1 µM), JNJ-2482272 had plasma concentrations beneath the lower limit of quantification (3 ng/ml) after 6 consecutive days of dosing. To determine if JNJ-2482272 is an autoinducer in rats, plated rat hepatocytes were treated with JNJ-2482272 for 2 days. The major hydroxylated metabolites of JNJ-2482272 were isolated and characterized by mass spectrometry and NMR analyses. Compared with the vehicle-treated cells, a concentration-dependent increase was observed in the formation of phase I- and II-mediated metabolites coinciding with greater expression of cytochrome P450s (P450s) and UDP-glucuronosyltransferases (UGTs) in rat hepatocytes. CYP1A1, CYP1A2, CYP1B1, and UGT1A6 transcripts were predominantly induced, suggesting that JNJ-2482272 is an activator of the aryl hydrocarbon receptor (AhR). In a human AhR reporter assay, JNJ-2482272 demonstrated potent AhR activation with an EC50 value of 0.768 nM, a potency more comparable to the strong AhR activator and toxin 2,3,7,8-tetrachloro-dibenzodioxin than to weaker AhR activators 3-methylcholanthrene, ß-naphthoflavone, and omeprazole. In plated human hepatocytes, JNJ-2482272 induced CYP1A1 gene expression with an EC50 of 20.4 nM and increased CYP1A activity >50-fold from basal levels. In human recombinant P450s, JNJ-2482272 was exclusively metabolized by the CYP1 family of enzymes and most rapidly by CYP1A1. The summation of these in vitro findings bridges the in vivo conclusion that JNJ-2482272 is a strong autoinducer in rats and potentially in humans through potent AhR activation. SIGNIFICANCE STATEMENT: Drugs that induce their own metabolism (autoinducers) can lack sustained exposures for pharmacology and safety assessment hindering their development. JNJ-2482272 is demonstrated herein as a strong aryl hydrocarbon receptor (AhR) activator and CYP1A autoinducer, explaining its near complete loss of exposure after repeat administration in rat, which is likely translatable to human (if progressed further) considering its nanomolar potency comparable to "classical" AhR ligands like 2,3,7,8-tetrachloro-dibenzo-dioxin despite bearing a "nonclassical" drug structure.

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We compare differences in the reproductive strategies of "free-living" dogs with their wild relatives in the genus Canis, of which the dog is a very recently evolved member. The members of this genus display a greater range of parental motor patterns than generally seen in other species of Carnivora, including pair-bonding and extended parental care; parents regurgitate to offspring and provision them with food for months to as long as a year. But the domestic dog does not routinely display these genus-typical behaviors. While this has generally been assumed to be a result of direct human intervention, humans have little reproductive control over the vast majority of domestic dogs. We analyze the low frequency of display of genus-typical behaviors and postulate that the dog's reproductive behaviors are an adaptation to permanent human settlement and the waste resources associated with it. Adaptation to this environment has decreased seasonality, increased the fecundity of unrestrained dogs and reduced the need for prolonged parental care. The consequences of greater fecundity and reduced parental care are compared to the reproductive behavior of other species of the genus.

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The pre-clinical characterization of novel aryloxypyridine amides that are histamine H(3) receptor antagonists is described. These compounds are high affinity histamine H(3) ligands that penetrate the CNS and occupy the histamine H(3) receptor in rat brain. Several compounds were extensively profiled pre-clinically leading to the identification of two compounds suitable for nomination as development candidates.

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A series of small molecules consisting of a heterocyclic core flanked by two basic functionalities were synthesized and screened for in vitro affinity at the human histamine H(3) receptor (hH(3)R). Nine of the twenty-eight compounds tested were found to possess a hH(3)R K(i) of less than 5 nM and consisted of a diverse range of central hetero-aromatic linkers (pyridine, pyrazine, oxazole, isoxazole, thiazole, furan, thiophene, and pyrrole). One member of this series, (4-isopropyl-piperazin-1-yl)-(6-piperidin-1-ylmethyl-pyridin-3-yl)-methanone (37), was found to be a high affinity, selective antagonist that crosses the blood-brain barrier and occupies H(3) receptors after oral administration in the rat.

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Barking is most often associated with the domestic dog Canis familiaris, but it is a common mammalian and avian vocalization. Like any vocalization, the acoustic character of the bark is likely to be a product of adaptation as well as an expression of the signaler's internal motivational state. While most authors recognize that the bark is a distinct signal type, no consistent description of its acoustic definition or function is apparent. The bark exhibits considerable variability in its acoustic form and occurs in a wide range of behavioral contexts, particularly in dogs. This has led some authors to suggest that dog barking might be a form of referential signaling, or an adaptation for heightened capability to communicate with humans. In this paper we propose a general 'canonical' acoustic description of the bark. Surveying relevant literature on dogs, wild canids, other mammals and birds, we explore an alternative functional hypothesis, first suggested by [Morton, E.S., 1977. On the occurrence and significance of motivation-structural rules in some bird and mammal sounds. Am. Nat. 111, 855-869] and consistent with his motivational-structural rules theory: that barking in many animals, including the domestic dog, is associated with mobbing behavior and the motivational states that accompany mobbing.

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The synthesis and biological activity of a new series of 2-aryloxymethylmorpholine histamine H(3) antagonists is described. The new compounds are high affinity histamine H(3) ligands that penetrate the CNS and occupy the histamine H(3) receptor in rat brain.

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