11 research outputs found
Chapitre 18. La lecture et les groupes particuliers
Rapprocher les livres des lecteurs isolés lorna knight Au cours du XXe siècle, la nature de l’isolement et, par conséquent, le type de lecteurs isolés ont changé de façon marquée, alors que la population canadienne, surtout rurale à l’origine et ayant peu accès aux livres, s’est grandement urbanisée. Les communautés éloignées ont été desservies par des réseaux de bibliothèques régionales subventionnés par le gouvernement provincial et par des clubs du livre étrangers et canadiens. Pour les co..
Discovery of Allosteric, Potent, Subtype Selective, and Peripherally Restricted TrkA Kinase Inhibitors
Tropomyosin receptor kinases (TrkA,
TrkB, TrkC) are activated by
hormones of the neurotrophin family: nerve growth factor (NGF), brain
derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and neurotrophin
4 (NT4). Moreover, the NGF antibody tanezumab has provided clinical
proof of concept for inhibition of the TrkA kinase pathway in pain
leading to significant interest in the development of small molecule
inhibitors of TrkA. However, achieving TrkA subtype selectivity over
TrkB and TrkC via a Type I and Type II inhibitor binding mode has
proven challenging and Type III or Type IV allosteric inhibitors may
present a more promising selectivity design approach. Furthermore,
TrkA inhibitors with minimal brain availability are required to deliver
an appropriate safety profile. Herein, we describe the discovery of
a highly potent, subtype selective, peripherally restricted, efficacious,
and well-tolerated series of allosteric TrkA inhibitors that culminated
in the delivery of candidate quality compound <b>23</b>
Discovery of Allosteric, Potent, Subtype Selective, and Peripherally Restricted TrkA Kinase Inhibitors
Tropomyosin receptor kinases (TrkA,
TrkB, TrkC) are activated by
hormones of the neurotrophin family: nerve growth factor (NGF), brain
derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and neurotrophin
4 (NT4). Moreover, the NGF antibody tanezumab has provided clinical
proof of concept for inhibition of the TrkA kinase pathway in pain
leading to significant interest in the development of small molecule
inhibitors of TrkA. However, achieving TrkA subtype selectivity over
TrkB and TrkC via a Type I and Type II inhibitor binding mode has
proven challenging and Type III or Type IV allosteric inhibitors may
present a more promising selectivity design approach. Furthermore,
TrkA inhibitors with minimal brain availability are required to deliver
an appropriate safety profile. Herein, we describe the discovery of
a highly potent, subtype selective, peripherally restricted, efficacious,
and well-tolerated series of allosteric TrkA inhibitors that culminated
in the delivery of candidate quality compound <b>23</b>
Discovery of Potent, Selective, and Peripherally Restricted Pan-Trk Kinase Inhibitors for the Treatment of Pain
Hormones
of the neurotrophin family, nerve growth factor (NGF),
brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and
neurotrophin 4 (NT4), are known to activate the family of Tropomyosin
receptor kinases (TrkA, TrkB, and TrkC). Moreover, inhibition of the
TrkA kinase pathway in pain has been clinically validated by the NGF
antibody tanezumab, leading to significant interest in the development
of small molecule inhibitors of TrkA. Furthermore, Trk inhibitors
having an acceptable safety profile will require minimal brain availability.
Herein, we discuss the discovery of two potent, selective, peripherally
restricted, efficacious, and well-tolerated series of pan-Trk inhibitors
which successfully delivered three candidate quality compounds <b>10b</b>, <b>13b</b>, and <b>19</b>. All three compounds
are predicted to possess low metabolic clearance in human that does
not proceed via aldehyde oxidase-catalyzed reactions, thus addressing
the potential clearance prediction liability associated with our current
pan-Trk development candidate PF-06273340
Discovery of Potent, Selective, and Peripherally Restricted Pan-Trk Kinase Inhibitors for the Treatment of Pain
Hormones
of the neurotrophin family, nerve growth factor (NGF),
brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and
neurotrophin 4 (NT4), are known to activate the family of Tropomyosin
receptor kinases (TrkA, TrkB, and TrkC). Moreover, inhibition of the
TrkA kinase pathway in pain has been clinically validated by the NGF
antibody tanezumab, leading to significant interest in the development
of small molecule inhibitors of TrkA. Furthermore, Trk inhibitors
having an acceptable safety profile will require minimal brain availability.
Herein, we discuss the discovery of two potent, selective, peripherally
restricted, efficacious, and well-tolerated series of pan-Trk inhibitors
which successfully delivered three candidate quality compounds <b>10b</b>, <b>13b</b>, and <b>19</b>. All three compounds
are predicted to possess low metabolic clearance in human that does
not proceed via aldehyde oxidase-catalyzed reactions, thus addressing
the potential clearance prediction liability associated with our current
pan-Trk development candidate PF-06273340
History of the Book in Canada. Volume III : 1918-1980
"The History of the Book in Canada is one of this country's great scholarly achievements, with three volumes spanning topics from Aboriginal communication systems established prior to European contact to the arrival of multinational publishing companies. Each volume observes developments in the realms of writing, publishing, dissemination, and reading, illustrating the process of a fledgling nation coming into its own. The third and final volume follows book history and print culture from the end of the First World War to 1980, discussing the influences on them of the twentieth century, including the country's growing demographic complexity and the rise of multiculturalism." -- Front flap of jacket