Novel triazolo-pyrrolopyridines as inhibitors of Janus kinase 1.

The identification of a novel fused triazolo-pyrrolopyridine scaffold, optimized derivatives of which display nanomolar inhibition of Janus kinase 1, is described. Prototypical example 3 demonstrated lower cell potency shift, better permeability in cells and higher oral exposure in rat than the corresponding, previously reported, imidazo-pyrrolopyridine analogue 2. Examples 6, 7 and 18 were subsequently identified from an optimization campaign and demonstrated modest selectivity over JAK2, moderate to good oral bioavailability in rat with overall pharmacokinetic profiles comparable to that reported for an approved pan-JAK inhibitor (tofacitinib).

Discovery and optimization of C-2 methyl imidazopyrrolopyridines as potent and orally bioavailable JAK1 inhibitors with selectivity over JAK2.

Herein we report the discovery of the C-2 methyl substituted imidazopyrrolopyridine series and its optimization to provide potent and orally bioavailable JAK1 inhibitors with selectivity over JAK2. The C-2 methyl substituted inhibitor 4 exhibited not only improved JAK1 potency relative to unsubstituted compound 3 but also notable JAK1 vs JAK2 selectivity (20-fold and >33-fold in biochemical and cell-based assays, respectively). Features of the X-ray structures of 4 in complex with both JAK1 and JAK2 are delineated.

Segregation, civil rights, and health disparities: the legacy of African American physicians and organized medicine, 1910-1968.

Between 1910 and 1968, the National Medical Association (NMA) repeatedly clashed with the American Medical Association (AMA) over the latter organization's racial bars to membership and other health policy issues. The NMA, founded in 1895 as a nonexclusionary medical society to provide a voice for disenfranchised black physicians and patients, struggled in its early years, during which AMA leadership took scant notice of it. But skirmishes ensued over such actions as stigmatizing racial labels in the AMA's American Medical Directory, which, beginning in 1906, listed all U.

Creating a segregated medical profession: African American physicians and organized medicine, 1846-1910.

An independent panel of experts, convened by the American Medical Association (AMA) Institute for Ethics, analyzed the roots of the racial divide within American medical organizations. In this, the first of a 2-part report, we describe 2 watershed moments that helped institutionalize the racial divide. The first occurred in the 1870s, when 2 medical societies from Washington, DC, sent rival delegations to the AMA's national meetings: an all-white delegation from a medical society that the US courts and Congress had formally censured for discriminating against black physicians; and an integrated delegation from a medical society led by physicians from Howard University.