Development of Novel Therapeutics for Glaucoma UMN-Mayo Partnership Project Update
Overview • Glaucoma – leading cause of irreversible blindness • Causal and most prevalent risk factor is elevated IOP • All treatments are aimed at reducing IOP • ATP-sensitive potassium channel openers • Lower IOP in ex vivo and in vivo models • Commercial compounds are not water-soluble
• Development of soluble prodrugs • Cromakalim was conducive to chemical modifcication
• CKLP1 is lead compound • Water solubility • Lowers IOP in ex vivo model and in vivo in mice
Vasodilator for acute/malignant hypertension, congenital hyperinsulinism, angina, etc.
KATP channel opener diazoxide & nicorandil lowers IOP through the Kir6.2/SUR2B subunit containing KATP channels Molecular structure of cromakalim is more conducive to chemical modifications that may make it more therapy friendly
Roy Chowdhury U et al. IOVS 2011, 2013 (Page 5)
Human anterior segment culture system Monitor pressure
Perfuse media
Pressure (mmHg)
40 35 30 25 20 15 10 5 0 0
1
2
3
4
5
6
7
8
Time (Days)
Conventional outflow pathway One-way fluid flow Pressure dependent Only human model (Page 6)
Pressure change (ex vivo) 30 Pressure (mmHg)
25
CKL
DMEM
20 15 10 5
Vehicle DMEM
0 CKL (2 µM) Vehicle
0
6
12
18
24
Time (1hr)
30
36
42
48
(Representative graph)
(Page 7)
CKL, CKLP1 lowers pressure (ex vivo)
CKL
CKLP1
35
35
n=11
Pressure (mmHg)
25
*
20 15 10 5
0h
24 h
0h
24 h
0
30 25
Pressure (mmHg)
30
n=5
*
20 15 10 5
0h
24 h
0h
24 h
0
Vehicle
CKL
Vehicle: 15.6 ± 4.9 to 15.6 ± 4.4 mmHg, (p=1.0) CKL: 19.3 ± 2.6 to 12.6 ± 3.0 mmHg, (p<0.001*)
Optically active CKLP1 in mice (historical data from glaucoma therpeutics) 2 1 0
ΔIOP
-1 -2 -3 -4 CKL (n=5)
-5
CKL-P1 (R) (n=5) (+)CKL-P1 (n=10)
-6 1
2 Baseline
3
4
5
6
7
8
CKL (various forms)
9
10
11
12
13
Post treatment
Figure 2. Comparison of cromakalim and cromakalim prodrugs. Treatment of C57BL/6 mice with the optically active form of CKLP1 resulted in a pressure reduction that is similar to the parent compound cromakalim. The racemic form of CKLP1 also caused a pressure reduction however it was less than the optically active form of CKLP1 and cromakalim.
Whitlock et al. Journal of Ocular Pharmacology and Therapeutics, 25, 2009, 187.
Page 2 of 10. Overview. ⢠Glaucoma â leading cause of irreversible blindness. ⢠Causal and most prevalent risk factor is elevated. IOP. ⢠All treatments are aimed ...
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