Treating male senescence
The invention provides methods of treating male reproductive senescence comprising administering to a male in need thereof a necroptosis inhibitor, including inhibitors of RIP1, RIP3 or MLKL. The invention also provides pharmaceutical compositions comprising a necroptosis inhibitor and a second different drug for treating male senescence.
1. A method of treating male senescence comprising administering to a male in need thereof a necroptosis inhibitor.
2. The method of claim 1 wherein the necroptosis inhibitor is a RIP1, RIP3 or MLKL inhibitor.
3. The method of claim 1 wherein the necroptosis inhibitor is a RIP1 inhibitor.
4. The method of claim 1 wherein the necroptosis inhibitor is a RIP1 inhibitor selected from a compound of Table 1 or Table 2 or Table 3:
Table 1
5-((1H-indol3-yl)methyl)-3-methyl-2-thioxoimidazolidin-4-one (Nec-1)
(S)-phenyl(5-phenyl -4,5-dihydro-1H-pyrazol -1-yl)methanone
5-((1H-indol-3-yl)methyl)-3-methyl-2-thioxoimidazolidin-4-one (Nec-1s)
3-methyl-5-((7-methyl-1H-indol3-yl)methyl)imidazolidine-2,4-dione
(R)-5-((7-chloro-1H-indol3-yl)methyl)-3-methylimidazolidine-2,4-dione
(R)-5-((7-chloro-1H-indol3-yl)methyl)-3-(4-(3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylphenyl)butyl) imidazolidine-2,4-dione (Ponatinib-Nec1s)
(S)-2,2-dimethyl-1-(5-phenyl-4,5-dihydro-1H-pyrazol-1-yl) propan-1-on (GSK963)
(S)-2,2-dimethyl-1-(5-phenyl-4,5-dihydro-1H-pyrazol-1-yl) propan-1-one
(S)-1-(4-(5-phenyl-4,5-dihydro-1H-pyrazole-1-carbonyl) piperidin-1-yl)ethanone
(S)-2,2-dimethyl-1-(5-(pyridin-2-yl)-4,5-dihydro-1H-pyrazol-1 -yl)propan-1-one
(S)-1-(4-(5-(3 ,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1 -carbonyl)piperidin-1-yl)ethanone
(S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)isoxazole-3-carboxamide
5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide
(S)-5-benzyl-N-(8-chloro-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide
(S)-5-benzyl-N-(5-methyl-4-oxo-7-(1H-tetrazol-5 -yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl) isoxazole-3-carboxamide
8-bromo-4, 5-dihydro-1H-benzo[b]azepin-2(3H)-one
(S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3 -yl)isoxazole-3 -carboxamide (GSK481)
(S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b]-[1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide (GSK2982772)
1-(4-(4-aminofuro[2,3 -d]pyrimidin-5-yl)phenyl)-3 -(2-fluoro-5-(trifluoromethyl)phenyl)urea (Cpd27)
3-methyl-5-((7-methyl-1H-indol1-3-yl)methyl)imidazolidine-2,4-dione
(R)-5-((7-chloro-1H-indol1-3-yl)methyl)-3-methylimidazolidine-2,4-dione
3 -benzyl-6,7-dihydro-3H-cyclopenta[4,5]thieno[2,3-d]pyrimidin-4(5H)-one
N-(3-chloro-2,6-difluorobenzyl)-4-cyclopropyl-1,2,3-thiadiazole-5 -carboxamide
(S)-N-(1-(2-chloro-6-fluorophenyl)ethyl)-5 -cyano-1-methyl-1H-pyrrole-2-carboxamide
(S)-N-(1-(2-chloro-6-fluorophenyl)ethyl)-4-cyclopropyl -1,2, 3-thiadiazole-5-carboxamide
N-Benzyl -N-hydroxy-2,2-dimethylbutanamide
N-(4-Fluorobenzyl)-N-hydroxy-2,2-dimethylbutanamide
N-(2,4-Difluorobenzyl)-N-hydroxy-2,2-dimethylbutanamide
N-(3,4-Difluorobenzyl)-N-hydroxy-2,2-dimethylbutanamide
N-Hydroxy-2,2-dimethyl -N-(2,3,4-trifluorobenzyl)butanamide
N-Hydroxy-2,2-dimethyl -N-(3,4,5-trifluorobenzyl)butanamide
N-Hydroxy-2,2-dimethyl -N-(2,3,5-trifluorobenzyl)butanamide
(2-(3-fluorophenyl)pyrrolidin-1-yl)(1-(trifluoromethyl)cyclopentyl)methanone
(2-(3-fluorophenyl)pyrrolidin-1-yl)(1-(trifluoromethyl)cyclobutyl)methanone
(S)-1-(2,2-dimethylbut-3-enoyl)-4-phenylazetidin-2-one
(S)-2,2-dimethyl-1-(2-phenylazetidin-1-yl)but-3-yn-1-one
(S)-1-(2,2-dimethylbutanoyl)-4-phenylazetidin-2-one,
TABLE 2
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151
S1
S2
S3
S4
S5
S6
S7
S8
S9
S10
S11
S12
S13
S14
S15
S16
S17
S18
S19
S20
TABLE 3
1
2
3
4
5
6
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8
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78
S1
S2
S3
S4
S5
S6
S7
S8
S9
S10
S11
S12
S13
S14
S15
S16
S17
5. The method of claim 1 wherein the necroptosis inhibitor is a RIP3 inhibitor.
6. The method of claim 1 wherein the necroptosis inhibitor is a RIP3 inhibitor selected from a compound of Table 4:
Table 4
tert-butyl 2-(4-(5-(methylcarbamoyl)-1H-benzo[d]imidazol-1-yl)phenyl)acetate (GSK'840)
3-(benzo[d]thiazol-5-yl)-7-(1,3-dimethyl-1H-pyrazol-5-yl)thieno[3,2-c]pyridin-4-amine GSK'843);
N-(6-(isopropylsulfonyl)quinolin-4-yl)benzo[d]thiazol-5-amine (GSK'872);
N-[3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-4-thiazolyl]-2-fluorophenyl]-2,6-difluoro-benzenesulfonamide (Dabrafenib);
3-(2-Imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[4-[(4-methyl-1-piperazinyl)methyl]-3-(trifluoromethyl)phenyl]-benzamide (ponatinib); or
5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methyl-benzenesulfonamide (pazopanib).
7. The method of claim 1 wherein the necroptosis inhibitor is a MLKL inhibitor.
8. The method of claim 1 wherein the necroptosis inhibitor is a MLKL inhibitor selected from a compound of Table 5 or Table 6 or Table 7:
Table 5
(2E)-N-[4-[[(3-Methoxy-2-pyrazinyl)amino]sulfonyl]phenyl]-3-(5-nitro-2-thienyl)-2-propenamide (Necrosulfonamide)
1,3,7-trimethyl-8-(methylsulfonyl)-1H-purine-2,6(3H,7H)-dione (TC13-4)
(2,5-dimethoxybenzylsulfonyl)-1,3,7-trimethyl-1H-purine-2,6(3H,7H)-dione (TC13-58)
7-ethyl-1,3-dimethyl-8-(methylsulfonyl)-1H-purine-2,6(3H,7H)-dione (TC13-74)
1,7-dimethyl-8-(methylsulfonyl)-3-(prop-2-ynyl)-1H-purine-2,6(3H,7H)-dione (TC13-106)
2-(1,7-dimethyl-8-(methylsulfonyl)-2,6-dioxo-1H-purin-3(2H,6H,7H)-yl)acetonitrile (TC13-107)
3-(3-(3-chlorophenyl)prop-2-yn-1-yl)-8-((cyclopropylmethyl) sulfonyl)-1,7-dimethyl-3,7-dihydro-1H-purine-2,6-dione (TC13-119)
8-((2,5-dimethoxybenzyl)sulfonyl)-1,7-dimethyl-3-(3-(2 -(methylamino)pyridin-4-yl)prop-2-yn-1-yl)-3,7-dihydro-1H-purine-2,6-dione (TC13-127)
3-(3-(3-hydroxyphenyl)prop-2-yn-1-yl)-1,7-dimethyl-8-(methylsulfonyl)-3,7-dihydro-1H-purine-2,6-dione (TC13-172)
3-((4-(methyl(4-(3-(4-(trifluoromethoxy)phenyl)ureido)phenyl)amino)pyrimidin-2-yl) amino)benzenesulfonamide (Compound 1)
TABLE 6
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2
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5
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126
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172
173
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175
176
TABLE 7
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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27
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29
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31
32
33
34
35
36
37
38
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40
41
42
43
44
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46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
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85
86
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91
92
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95
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120
9. The method of claim 1 wherein the method further comprises administering to the male a second, different drug for treating male senescence.
10. The method of claim 1 wherein the method further comprises administering to the male a second, different drug for treating male senescence, wherein the different drug is selected from an androgen including exogenous and endogenous anabolic androgenic steroids, endogenous androgen stimulators, female hormone inhibitor, growth hormone.
11. The method of claim 1 wherein the method further comprises administering to the male a second, different drug for treating male senescence, wherein the different drug is selected from:
testosterone, prasterone (dehydroepiandrosterone, DHEA), androstenedione (A4), androstenediol (A5), dihydrotestosterone (DHT), 1-Androstenediol, 1-Androstenedione, Bolandiol, Bolasterone, Boldenone, Boldione, Calusterone, Clostebol, Danazol, Dehydrochlormethyltestosterone, Desoxymethyltestosterone, Drostanolone, Ethylestrenol, Fluoxymesterone, Formebolone, Furazabol, Gestrinone, 4-Hydroxytestosterone, Mestanolone, Mesterolone, Metenolone, Methandienone, Methandriol, Methasterone, Methyldienolone, Methyl-1-testosterone, Methylnortestosterone, Methyltestosterone, Metribolone, Mibolerone, Nandrolone, 19-Norandrostenedione, Norboletone, Norclostebol, Norethandrolone, Oxabolone, Oxandrolone, Oxymesterone, Oxymetholone, Prostanozol, Quinbolone, Stanozolol, Stenbolone, 1-Testosterone, Tetrahydrogestrinone, and Trenbolone.
12. The method of claim 1 wherein the male senescence is selected from age-associated low testosterone, low libido, erectile dysfunction, weight gain, reduced muscle mass or tone, and prostate hyperplasia.
13. The method of claim 1 wherein the method further comprises the antecedent step of diagnosis the male senescence.
14. The method of claim 1 wherein the method further comprises the subsequent step of detecting a resultant diminution or reversal of the male senescence.
15. The method of claim 3 wherein the method further comprises the subsequent step of detecting a resultant diminution or reversal of the male senescence.
16. The method of claim 4 wherein the method further comprises the subsequent step of detecting a resultant diminution or reversal of the male senescence.
17. The method of claim 5 wherein the method further comprises the subsequent step of detecting a resultant diminution or reversal of the male senescence.
18. The method of claim 6 wherein the method further comprises the subsequent step of detecting a resultant diminution or reversal of the male senescence.
19. The method of claim 7 wherein the method further comprises the subsequent step of detecting a resultant diminution or reversal of the male senescence.
20. The method of claim 8 wherein the method further comprises the subsequent step of detecting a resultant diminution or reversal of the male senescence.