Discovery of INCB3284, a Potent, Selective, and Orally Bioavailable hCCR2 Antagonist.

We report the identification of 13 (INCB3284) as a potent human CCR2 (hCCR2) antagonist. INCB3284 exhibited an IC50 of 3.7 nM in antagonism of monocyte chemoattractant protein-1 binding to hCCR2, an IC50 of 4.7 nM in antagonism of chemotaxis activity, an IC50 of 84 µM in inhibition of the hERG potassium current, a free fraction of 58% in protein binding, high selectivity over other chemokine receptors and G-protein-coupled receptors, and acceptable oral bioavailability in rodents and primates. In human clinical trials, INCB3284 exhibited a pharmacokinetic profile suitable for once-a-day dosing (T 1/2 = 15 h).

Metabolism, excretion, and pharmacokinetics of [14C]INCB018424, a selective Janus tyrosine kinase 1/2 inhibitor, in humans.

The metabolism, excretion, and pharmacokinetics of 3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile (INCB018424), a potent, selective inhibitor of Janus tyrosine kinase1/2 and the first investigational drug of its class in phase III studies for the treatment of myelofibrosis, were investigated in healthy human subjects given a single oral 25-mg dose of [(14)C]INCB018424 as an oral solution. INCB018424 and total radioactivity were absorbed rapidly (mean time to reach the maximal drug concentration <1 h), declining in a monophasic or biphasic fashion (mean t(1/2) of 2.32 and 5.81 h, respectively). Recovery of administered radioactivity was fairly rapid (>70% within 24 h postdose) with 74 and 22% recovered in urine and feces, respectively. Parent compound was the predominant entity in the circulation, representing 58 to 74% of the total radioactivity up to 6 h postdose, indicating that the overall circulating metabolite burden was low (<50% of parent). Two metabolite peaks in plasma (M18 and a peak containing M16/M27, both hydroxylations on the cyclopentyl moiety) were identified as major (30 and 14% of parent based on area under the curve from 0 to 24 h). The exposures of other circulating INCB018424-related peaks were <10% of parent, consisting of mono- and dihydroxylated metabolites. The profiles in urine and feces consisted of hydroxyl and oxo metabolites and subsequent glucuronide conjugates with parent drug accounting for <1% of the excreted dose, strongly suggesting that after an oral dose, INCB018424 was >95% absorbed. In healthy subjects administered daily oral doses of unlabeled INCB018424, there were minimal differences in parent and metabolite concentrations between day 1 and day 10, indicating a lack of accumulation of parent or metabolites between single and multiple dosing.

Asymmetric synthesis of the (S)-1,1-dioxido-isothiazolidin-3-one phosphotyrosine mimetic via reduction of a homochiral (R)-oxido-isothiazolidin-3-one.

[structure: see text]. The first asymmetric synthesis of the (S)-1,1-dioxido-isothiazolidin-3-one ((S)-IZD) pTyr mimetic, which has been incorporated into the recently reported potent protein tyrosine phosphatase 1B (PTP1B) inhibitors, is presented herein. The key reaction is the reduction of the (R)-oxido-isothiazolidin-3-one heterocycle with excellent regiochemical and stereochemical control (>98% ee; 82% yield).