Selective factor VIIa-tissue factor complex (FVIIa/TF) inhibition is regarded as a promising target for developing new anticoagulant drugs. In previous reports, we described a S3 subsite found in the X-ray crystal structure of compound 2 that bound to FVIIa/soluble tissue factor (sTF). Based on the X-ray crystal structure information and with the aim of improving the inhibition activity for FVIIa/TF and selectivity against other serine proteases, we synthesized derivatives by introducing substituents at position 5 of the indole ring of compound 2. Among them, compound 16 showed high selectivity against other serine proteases. Contrary to our expectations, compound 16 did not occupy the S3-subsite; X-ray structure analysis revealed that compound 16 improved selectivity by forming hydrogen bonds with Gln217, Thr99 and Asn100.
The title compound, C9H15N5O, is an antialopecia agent. The crystal belongs to space group P21 with cell dimensions a = 9.3799(5) , b = 8.3319(4), c = 12.9984(7)Å and β = 90.191(3)°. The final R value is 0.092. There are two crystallographically independent molecules in an asymmetric unit. They adopt significantly different conformations. The hybridization states of the nitrogen atoms in piperidine rings are markedly different in these molecules.