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. Author manuscript; available in PMC: 2015 Nov 15.
Published in final edited form as: J Med Chem. 2014 Dec 4;57(24):10314–10328. doi: 10.1021/jm500902x

Table 4.

Comparative SAR, Physiochemical, and In Vitro ADME Data for Select Analogs

solubility
(µM)g 		aqueous
stability (%)j,k
entry analog RSV CPE potency
± standard
deviation EC50
(µM)a 		HEp-2 cellular
toxicity ± standard
deviation CC50
(µM)d 		selectivity
index
(CC50/ EC50)		 viral titer
reduction at
10 µM (log)		 PBSh mediai PBS 1:1
PBS/
ACN		 Pe, PAMPA
permeability
(×10−6 cm/s)g,l 		hepatocyte
toxicity
LC50
(µM)g,o
1 2 2.1 ± 0.5 >50.0 23.8 4.2 0.1 NT 88.1 94.0 NT NT
2 15 0.5 ± 0.05b >50.0b >100 5.6f 1.3 2.8 83.4 94.9 364/349/356m >50
3 19 0.3 ± 0.03c >50.0c,e >166.7 6.7 0.4 10.2 27.0 100 718/631/703n >30
4 46 1.1 ± 0.2 44.7 ± 7.2 41.8 >6.2 11.2 18.5 90.2 100 780/686/514m >50
a

Data were an average of ≥3 experiments.

b

Data were an average of outcomes from three separate lots of compound 15.

c

Data were an average of outcomes from two separate lots of compound 19.

d

Data are an average of ≥2 experiments.

e

Data were obtained from a 3-day exposure experiment versus 5-day duration due to precipitation of compound after 3 days.

f

Data were an average of outcomes from two separate lots of compound 15.

g

Data collected by Ms. Arianna Mangravita-Novo at the Conrad Prebys Sanford Burnham Medical Research Institute.

h

Kinetic solubility in 1× PBS, pH 7.4.

i

Kinetic solubility in CPE assay media: (DMEM/F12(r) (Sigma, Cat # D6434)/1× Pen/Strep/Glutamine (Gibco, Cat # 10378)/2% Heat Inactivated FBS (Gibco Cat # 10082)).

j

Data collected by Mr. Patrick Porubsky at the University of Kansas Analytical Chemistry Core, Specialized Chemistry Center.

k

Results are represented as percent parent remaining after 48 h; Stability assessment was done independently in PBS or with 1:1 PBS and acetonitrile; the latter was used to account for limitations in solubility affecting PBS results.

l

PAMPA donor pH: 5.0/6.2/7.4, acceptor pH: 7.4; controls: verapamil (222/1097/1936–highly permeable), metoprolol (14/60/472–moderately permeable), ranitidine (<10/<10/<10–poorly permeable).

m

PAMPA done in PBS, no additives.

n

PAMPA done with 20% acetontrile added to compensate for PBS solubility. Without acetonitrile, Pe was insignificant at each pH.

o

Fa2N-4 immortalized human hepatocytes. Data were analyzed using Microsoft Excel 2010;

NT = not tested.