TABLE 1

Propargyl-linked antifolates synthesized to reduce P450 inhibition imparted through the unsubstituted pyridine of compound 11

The intrinsic clearance is reported for the two substrate concentrations tested, 5 and 0.5 µg/ml.

ScaffoldCompoundStereochemistryB-RingC-RingMICMLM CLintCYP3A4CYP2D6
5 µg/ml0.5 µg/ml
µg/mlµl/min/mgµl/min/mgµMµM
Embedded Image10RacemicEmbedded ImageEmbedded Image0.62521
11SEmbedded ImageEmbedded Image0.07810990.051.6
12RacemicEmbedded ImageEmbedded Image0.156401733.69.8
13RacemicEmbedded ImageEmbedded Image0.156692.613.2
14RacemicEmbedded ImageEmbedded Image0.3121541112.9
15RacemicEmbedded ImageEmbedded Image0.62522>50>50
16RacemicEmbedded ImageEmbedded Image0.156690.527.4
17RacemicEmbedded ImageEmbedded Image0.3122543>50
18RacemicEmbedded ImageEmbedded Image0.625285.4>50
19SEmbedded ImageEmbedded Image0.1561841>50