The Discovery of a Potent, Selective, and Peripherally Restricted Pan-Trk Inhibitor (PF-06273340) for the Treatment of Pain

The neurotrophin family of growth factors, comprised of nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and neurotrophin 4 (NT4), is implicated in the physiology of chronic pain. Given the clinical efficacy of anti-NGF monoclonal antibody (mAb) therapies, there is significant interest in the development of small molecule modulators of neurotrophin activity. Neurotrophins signal through the tropomyosin related kinase (Trk) family of tyrosine kinase receptors, hence Trk kinase inhibition represents a potentially “druggable” point of intervention. To deliver the safety profile required for chronic, nonlife threatening pain indications, highly kinase-selective Trk inhibitors with minimal brain availability are sought. Herein we describe how the use of SBDD, 2D QSAR models, and matched molecular pair data in compound design enabled the delivery of the highly potent, kinase-selective, and peripherally restricted clinical candidate PF-06273340

Le panthéon de l'Arabie du sud préislamique : état des problèmes et brève synthèse

The Pantheon of Pre-Islamic Southern Arabia 'Athtar, a male Venus-god of irrigation and thunderstorm, had superseded the ancient Semitic supreme god Il as the head of the pantheon, in which the astral element was far from being exclusive. Moreover, each kingdom has its own national god : a male sun-god of irrigation, an imaginary ancestor of the nation and/or of its ruler, or a sun-goddess. The gods appear frequently with a consort of the opposite sex. Specific divinities for each kingdom, frequently known only by name, were in charge of irrigation, the healing of sickness, etc. The monumental inscriptions (exclusive of any mythological literature) and a limited iconography do not allow to construct a system from this meagre data.'Athtar, dieu-Vénus masculin de l'irrigation et de l'orage, avait supplanté l'ancien dieu suprême sémitique Il à la tête du panthéon, où le rôle de l'élément astral est loin d'avoir été exclusif. Chaque royaume avait en outre son dieu national : dieu-Soleil de l'irrigation, ancêtre fictif de la nation et/ou de son souverain, ou déesse-Soleil. Les divinités formaient souvent un couple dieu-déesse. Des dieux particuliers à chaque Etat, dont on ne connaît souvent que le nom, présidaient à l'irrigation, à la guérison des maladies, etc. Les inscriptions monumentales (où manque toute littérature mythologique), ainsi qu'une iconographie réduite ne permettent guère de structurer ces maigres données.Ryckmans Jacques. Le panthéon de l'Arabie du sud préislamique : état des problèmes et brève synthèse. In: Revue de l'histoire des religions, tome 206, n°2, 1989. pp. 151-169

5-Aminopyrazoles from enolisable ketones and 1-cyano-1-alkylhydrazines.

The reaction of enolisable ketones with 1-alkyl-1-cyanohydrazines leads to the corresponding cyanohydrazones. These compounds cyclise under thermal or mildly basic conditions, furnishing the corresponding 5-aminopyrazoles in good yield. In some cases, the hydrazones cannot be isolated and the pyrazole derivatives are directly obtained. Hydrazone-enehydrazine tautomerism was observed, bat no subsequent [3,3]rearrangement. (C) 1997, Elsevier Science Ltd