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. Author manuscript; available in PMC: 2020 Feb 14.
Published in final edited form as: J Med Chem. 2019 Jan 24;62(3):1562–1576. doi: 10.1021/acs.jmedchem.8b01754

Table 5.

Evaluation of substitutions on the distal pyrimidine ring of 26 on DHFR inhibition, selectivity, solubility, human liver microsomal clearance and MDCK-MDR-1 permeability

graphic file with name nihms-1031777-t0004.jpg
Compound R3 TgDHFRa
IC50 (nM)		 hDHFRa
IC50 (nM)		 Selectivity indexb Solubility
(μM)c 		HLMd
(CLint)		 MDR1-MDCKe
29 Me 3.95 ± 0.26 935 ± 46 237 150 <8.6 19.3 (1.2)
3 MeO 1.57 ± 0.42 308 ± 71 196 186 <8.6 20.1 (1.1)
30 CF3 32.7 ± 3.3 2800 ± 470 85.6 17 10.5 --
31 cypropyl 9.92 ± 0.83 973 ± 120 98 12 17.4 --
a

Average of at least 3 independent replicates ± SEM.

b

Selectivity index (SI) is the hDHFR IC50/TgDHFR IC50, determined within the same experiment.

c

Kinetic solubility.

d

HLM human liver microsomes, CLint intrinsic clearance (mL/min/kg),

e

A:B permeability (papp 10−6 cm/sec), where ER is efflux ratio defined as permeability in A:B/B:A directions.