Table 1 Medicinal chemistry progression of the screening hit 1 to VX-147

From: Small molecule APOL1 inhibitors as a precision medicine approach for APOL1-mediated kidney disease

 

Compound 1

Compound 2

Compound 3

Compound 4

LogD7.4

5.0

2.8

2.7

2.7

APOL1 G1/G2 Thallium flux IC50 (nM)

580/ND (4)

40/ND (5)

4.2/5.4 (13/7)

2.0/1.2 (32 /4)

APOL1 G1/G2 HEK Cell Rescue EC50 (nM)

1100/ND (5)

37/ND (8)

3.6/10 (21/9)

2.0/2.2 (4/1)

Rat/human Clint (mL/min/106 cells)

> 400/259

8.2/15.4

5.1/6.3

4.7 / < 2.5

Rat Cl (mL/min/kg)

61

15

6.0

4.8

Rat t1/2

0.81

4.1

4.2

2.5

Rat Vd (L/kg)

1.6

2.1

1.4

0.9

Rat oral bioavailability (%)

11

34

28

57

  1. Reversal of the amide and installation of the aminolactam afforded compound 2 with increased potency and metabolic stability. Oxidation of the lactam to compound 3 further increased potency and metabolic stability. Further Structure-Activity-Relationship (SAR) investigation of the indole core gave VX-147 with optimized properties. In vitro efficacy replicates are shown in brackets. ND not determined, Vd volume of distribution, T1/2 half-life, Cl clearance.
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