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. Author manuscript; available in PMC: 2013 Apr 12.
Published in final edited form as: J Med Chem. 2012 Apr 3;55(7):3535–3545. doi: 10.1021/jm300214e

Table 1.

WEEV Replicon and Physical Property Data for New Analogs (Schemes 1 and 2)

No. R1 NR2R3 IC50 (µM)a CC50
(µM)b 		CC50/IC50 ClogPc Log Peffd MLM
T1/2
(min)e
1 4-F-Ph-CH2 NHCH2furan-2-ylNH 24.4 ± 6.9 >100 >4.1 3.05
5a 4-F-Ph-CH2 NHCH2Ph 25.4 ± 7.3 >100 >3.9 3.88
5b 4-Cl-Ph-CH2 NHCH2Ph 10.1 ± 2.6 >100 >9.9 4.45 −3.6 ±. 01 1.7 ± 1.7
5c 4-F-Ph-CH2 (S)-NHCH(CH3)Ph >100 >100 4.76
5d 4-F-Ph-CH2 (R)-NHCH(CH3)Ph 8.3 ± 1.3 93.4 11 4.76
5e (R)-4-F-PhCH(CH3) NHCH2Ph 18.4 ± 4.7 >100 >5.4 4.04
5f (S)-4-F-PhCH(CH3) NHCH2Ph >100 >100 4.04
9a 4-F-Ph-CH2 NHCH2Ph 14.8 ± 5.8 >100 >6.7 3.98
9b 4-Cl-Ph-CH2 NHCH2Ph 15.5 ± 5.6 >100 >6.5 4.55 −3.6 ± .03 7.3 ± 3.9
9c 4-Cl-Ph-CH2 NHCH2Phf 30.6 ± 7.3 >100 >3.3 5.71
9d 4-Cl-Ph-CH2 NHPh >50 NDg 4.92
9e 4-Cl-Ph-CH2 NHCH2CH2Ph 15.2 ± 9.3 62.1 4.1 4.62
9f 4-Cl-Ph-CH2 NHCH2CH2(4-Me-Ph) 5.5 ± 2.2 75.2 14 5.12 −3. 9± .11
9g 4-Cl-Ph-CH2 (S)-NHCH(CH3)Ph >100 >100 4.86
9h 4-Cl-Ph-CH2 (R)-NHCH(CH3)Ph 6.5 ± 1.5 89.9 14 4.86 −3.6 ± .03 31 ± 7.1
9i 4-Cl-Ph-CH2 NHCH2(4-MeO-Ph) >50 ND 4.47
9j 4-Cl-Ph-CH2 NHCH2(3-Cl-Ph) 15.3 ± 9.0 >100 >6.5 5.26
9k 4-Cl-Ph-CH2 N-piperidinyl 9.2 ± 2.8 51.7 5.6 3.58
9l 4-Cl-Ph-CH2 NHCH2pyridin-4-yl 6.8 ± 1.7 >100 >14 3.05 −3.7 ± .17
9m 4-Cl-Ph-CH2 NHCH2pyridin-3-yl 11.4 ± 0.4 >100 >8.7 3.05
a

Inhibition of luciferase expression in the WEEV replicon assay. Ribavirin (positive control) has an IC50 in this assay of 16 µM.

b

Cell viability as determined by inhibition of mitochondrial reduction of MTT.

c

Calculated logP (ChemBioDraw Ultra 11.0).

d

Log of effective permeability (cm/sec) as determined by PAMPA Explorer (pION).

e

Half-life in mouse liver microsome incubations.

f

The amide CONHCH2Ph is bonded to the 3-position of the piperidine instead of the 4-position.

g

ND: not determined.