WO1993007864A1 - Use of suramine and related compounds as contraceptive agents - Google Patents

Use of suramine and related compounds as contraceptive agents Download PDF

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Publication number
WO1993007864A1
WO1993007864A1 PCT/GB1992/001925 GB9201925W WO9307864A1 WO 1993007864 A1 WO1993007864 A1 WO 1993007864A1 GB 9201925 W GB9201925 W GB 9201925W WO 9307864 A1 WO9307864 A1 WO 9307864A1
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Prior art keywords
compound
formula
suramin
contraception
compounds
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PCT/GB1992/001925
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French (fr)
Inventor
Robert Jones
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British Technology Group Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Priority claimed from GB919122477A external-priority patent/GB9122477D0/en
Priority claimed from GB919124789A external-priority patent/GB9124789D0/en
Application filed by British Technology Group Ltd. filed Critical British Technology Group Ltd.
Publication of WO1993007864A1 publication Critical patent/WO1993007864A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids

Definitions

  • This invention relates to contraceptive compounds and their administration.
  • proacrosin present on spermatozoa, that mediates binding to the zona pellucida, the extracellular matrix that surrounds all mammalian eggs and to which spermatozoa must bind if they are to eventually fertilize the egg.
  • Proacrosin is present in all mammalian spermatozoa and there is reason to believe that its mechanism of action is similar across species.
  • proacrosin mediates binding of spermatozoa to the zona by recognizing polysulphate groups on carbohydrate chains of zona glycoproteins.
  • a method of contraception comprises administering to a mammal a non-toxic amount of a compound of formula I effective to prevent conception: (ABCD) 2 E n (I)
  • A represents A 1 or A 2
  • D represents D 1 , D 2 , D 3 , D 4 or D 5
  • E represents E 1 , E 2 or E 3
  • M represents hydrogen or an alkali metal e.g. sodium
  • R represents an alkyl group e.g. a C 1 -C 6 alkyl group such as methyl and
  • n o or l .
  • the amino compounds may be condensed with carbonyl chloride to yield a compound of formula I where D is D1 and E is E1 or further modified before final condensation to introduce moieties D 2 to D 5 and/or E2 or E3 to yield further compounds of formula I.
  • Compounds of formula I may be administered effectively to both males and females. At least when compound I represents Suramin, however, administration to males is more usual.
  • the dose rate required to achieve effective contraception varies of course with the mammal treated, the mammal's body weight, surface area, age and general state of health, but as a guide 0.04 mg/kg to 40 mg/kg represents a normal range, with 0.4 mg/kg to 4 mg/kg being more typical.
  • Veterinary application is of particular interest.
  • Administration may be by mouth or, less usually, parenterally including subcutaneously, intramuscularly, intravenously and topically.
  • Formulations of the present invention comprise the active compound together with one or more physiologically acceptable carriers thereof and, optionally, any other desired ingredients, for example of therapeutic utility.
  • the carrier(s) must be physiologically acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • Formulations include those suitable for oral, or parenteral (including subcutaneous, intramuscular and intravenous) administration.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include generally the step of bringing the active compound into association with a carrier with constitutes one or more accessory ingredients. Usually, the formulations are prepared by uniformly and intimately bringing the active compound into association with a liquid carrier or with a finely divided solid carrier or with both and then, if necessary, shaping the product into desired formulations.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, tablets or lozenges, each containing a predetermined amount of the active compound; as a powder or granules; or a suspension in an aqueous liquid or non-aqueous liquid such as a syrup, an elixir, an emulsion or a draught.
  • the active compound may also be presented as a bolus, electuary or paste.
  • a tablet may be made by compression or moulding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing, in a suitable machine, the active compound in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent.
  • Moulded tablets may be made by moulding, in a suitable machine, a mixture of the powdered active compound with any suitable carrier.
  • a syrup may be made by adding the active compound to a concentrated, aqueous solution of a sugar, for example sucrose, to which may be added any accessory ingredient.
  • a sugar for example sucrose
  • Such accessory ingredient(s) may include flavourings, an agent to retard crystallisation of the sugar or an agent to increase the solubility of any other ingredient, such as a polyhydric alcohol for example glycerol or sorbitol.
  • Formulations suitable for parental administration conveniently comprise a sterile aqueous preparation of the active compound which is preferably isotonic with the blood of the recipient.
  • Suramin is a potent inhibitor of the recognition and binding between sperm proacrosin and zona pellucida glycoproteins.
  • Toxicity data taken from "Inhibitions of HIV-Type 1 Reverse Transcriptase by Suramin-related compounds" (K.D. Jentsch et al. J. Gen. Virol (1987) 68, 2183-92) is also included. Briefly, this toxicity work measured the toxicity of the compounds by exposing MT4 cells, a human HTLV-1 bearing cell line, to differing concentrations of the compound under study. The lowest concentration which impaired cell growth (measured by thymidine incorporation) was given as a measure of toxicity. The results are given in Table 1 as Cell Impairing Growth Concentration.
  • Example 2 was repeated using various concentrations of the following compounds:

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

A method of contraception comprises administering to a mammal a non-toxic amount of the compound Suramin or a structurally-related polysulphonated compound.

Description

USE OF SURAMINE AND RELATED COMPOUNDS AS CONTRACEPTIVE AGENTS
This invention relates to contraceptive compounds and their administration.
Recently there has been identified a molecule proacrosin, present on spermatozoa, that mediates binding to the zona pellucida, the extracellular matrix that surrounds all mammalian eggs and to which spermatozoa must bind if they are to eventually fertilize the egg. Proacrosin is present in all mammalian spermatozoa and there is reason to believe that its mechanism of action is similar across species. As discussed by Jones, Development, 111, (1991), 1155-1163, proacrosin mediates binding of spermatozoa to the zona by recognizing polysulphate groups on carbohydrate chains of zona glycoproteins. Jones showed that, while binding could effectively be inhibited by sulphonated polymeric materials such as dextran sulphate and poly(vinyl sulphate), lower molecular weight materials such as low molecular weight dextran sulphate and glucosamine-2,3-disulphate were ineffective inhibitors.
It has now been found that a compound known as Suramin, and related compounds of comparatively low molecular weight which contain a plurality of sulphonate groups, can block sperm-zona binding in in vitro fertilization experiments with mice. These compounds therefore have potential as contraceptive agents.
In accordance with the present invention, a method of contraception comprises administering to a mammal a non-toxic amount of a compound of formula I effective to prevent conception: (ABCD)2En (I)
in which formula I:
A represents A1 or A2
Figure imgf000004_0001
Figure imgf000004_0002
B represents
(A)┄ NH·CQ┄ (C) C represents C1 or C2
Figure imgf000004_0003
Figure imgf000004_0004
D represents D1 , D2, D3, D4 or D5
D 1 (C)┄ NH┄ (E)
Figure imgf000005_0001
Figure imgf000005_0002
Figure imgf000005_0003
Figure imgf000005_0004
E represents E1 , E2 or E3
Figure imgf000005_0005
M represents hydrogen or an alkali metal e.g. sodium;
a + b = 1;
the dotted lines represent linkages to neighbouring groups shown in brackets;
c + d = o or l; e + f + g + h = o or l; R represents an alkyl group e.g. a C1-C6 alkyl group such as methyl and
n = o or l .
Typically, when C = C2, e, f and g = o and h = 1 and when C = C1 typically c + d = o.
Compounds of particular interest include the following compounds of formula I:
(a) A = A1, a = 1, b = o, M = Na, C = C2, R = CH3, e + f + g = o, h = l, R = CH3, D = D4, E = E| (Suramin)
(b) A = A1, a = o, b = 1, M = Na, C = C1, c + d = o, D = D1,
E-E1 (c) A = A1, a = o, b = 1 , M = Na, C = C1. c + d = o, D = D2,
E - E1
(d) A = A1, a = 1, b = o, M = Na, C = C2, e + f + g + h = o,
D = D3, E = E1
(e) A = A1, a = 1, b = o, M = Na, C = C2, e + f + g = o, h = 1, R = CH3, D = D4, E = E3
(f) A = A2, M = Na, C = C2, e + f + g = o, h = 1, R = CH3,
D = D4, E = E1
(g) A = A1, a = l, b = o, M = Na, C = C2, e + f + g + h = o,
D = D5, E = E1,
The structures of compounds (a) - (g) are as follows:
Figure imgf000007_0001
Figure imgf000007_0002
Figure imgf000007_0003
Figure imgf000008_0001
Figure imgf000008_0002
Figure imgf000008_0003
Figure imgf000008_0004
Compounds of formula I may be produced by adapting the method described in British Patent No. 224849 which describes the synthesis of the compound Suramin of formula (a) above. Compounds of formulae (b) to (g) are described by Jentsch et al, J. gen. Virol., (1987), 68, 2183-2192. In general the compounds of formula I may be synthesised as follows.
An amine of formula IIA or IIB:
Figure imgf000009_0002
Figure imgf000009_0001
where M, a and b are as defined above, is reacted with a compound IIIA or IIIB
Figure imgf000009_0003
Figure imgf000009_0004
where c, d, e, f, g and h are as defined above,
to produce, respectively, a compound IVA, IVB, IVC or IVD,
the nitro group of which compound, IVA, IVB, IVC or IVD is reduced to the corresponding amino group to give the corresponding amino compounds.
The amino compounds may be condensed with carbonyl chloride to yield a compound of formula I where D is D1 and E is E1 or further modified before final condensation to introduce moieties D2 to D5 and/or E2 or E3 to yield further compounds of formula I.
Compounds of formula I may be administered effectively to both males and females. At least when compound I represents Suramin, however, administration to males is more usual. The dose rate required to achieve effective contraception varies of course with the mammal treated, the mammal's body weight, surface area, age and general state of health, but as a guide 0.04 mg/kg to 40 mg/kg represents a normal range, with 0.4 mg/kg to 4 mg/kg being more typical. Veterinary application is of particular interest.
Administration may be by mouth or, less usually, parenterally including subcutaneously, intramuscularly, intravenously and topically.
While it is possible for the active compound I to be administered alone it is preferable to present the active compound as a formulation. Formulations of the present invention, for contraceptive use, comprise the active compound together with one or more physiologically acceptable carriers thereof and, optionally, any other desired ingredients, for example of therapeutic utility. The carrier(s) must be physiologically acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
Formulations include those suitable for oral, or parenteral (including subcutaneous, intramuscular and intravenous) administration.
The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include generally the step of bringing the active compound into association with a carrier with constitutes one or more accessory ingredients. Usually, the formulations are prepared by uniformly and intimately bringing the active compound into association with a liquid carrier or with a finely divided solid carrier or with both and then, if necessary, shaping the product into desired formulations.
Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, tablets or lozenges, each containing a predetermined amount of the active compound; as a powder or granules; or a suspension in an aqueous liquid or non-aqueous liquid such as a syrup, an elixir, an emulsion or a draught. The active compound may also be presented as a bolus, electuary or paste.
A tablet may be made by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing, in a suitable machine, the active compound in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Moulded tablets may be made by moulding, in a suitable machine, a mixture of the powdered active compound with any suitable carrier.
A syrup may be made by adding the active compound to a concentrated, aqueous solution of a sugar, for example sucrose, to which may be added any accessory ingredient. Such accessory ingredient(s) may include flavourings, an agent to retard crystallisation of the sugar or an agent to increase the solubility of any other ingredient, such as a polyhydric alcohol for example glycerol or sorbitol.
Formulations suitable for parental administration conveniently comprise a sterile aqueous preparation of the active compound which is preferably isotonic with the blood of the recipient.
The present invention is illustrated by the following Examples:
EXAMPLES
Example 1
Inhibition of binding of zona pellucida glycoproteins to
proacrosin by Suramin
Method. 5 μg of purified proacrosin (from boar spermatozoa) was immobilised by dot-blotting onto 1 cm2 nitrocellulose, the paper allowed to dry and non-specific binding sites blocked with 51 bovine serum albumin for 3 hrs at room temperature. Blots were then blocked with PBS (controls) or varying concentrations of suramin (1 μM - 64 μM) for 1 hr, drained and probed with 125I- labelled pig zona pellucida glycoproteins for a further hr. Unbound probe was washed away with PBS and bound probe counted in a gamma counter. The IC50 for Suramin was calculated from semi-log plots of inhibitor concentration against maximum specific binding activity.
Results. Results with Suramin gave an IC50 of 14.1 μM.
Conclusions. Suramin is a potent inhibitor of the recognition and binding between sperm proacrosin and zona pellucida glycoproteins.
Example 2
Anti-fertility tests with Suramin
Methods. Twenty-one day old female mice (CFLP strain) were injected i.p. with 5 IU of FSH (follicle stimulating hormone) followed 48 hours later by 5 IU of LH (luteinizing hormone) i.p.
Superovulated eggs within the cumulus masses were recovered from the oviduct 18 hours post LH and flushed into Medium 199.
Spermatozoa were collected from the vas deferens of adult males, suspended in Medium 199/0.1% bovine serum albumin and incubated at 37°C for 1 hour in air/CO2 (95%/5%). Spermatozoa were then diluted to approximately 105/ml, various concentrations of
Suramin added followed by cumulus egg masses. After 4 hours incubation at 37°C in air/CO2, eggs were collected, washed 3 times and the number of spermatozoa binding to the zona pellucida counted using phase contrast microscopy.
Results. Results with Suramin were as follows.
Control. 9.7 ± 4.8 sperm/egg (37 eggs total).
+ 1 μM Suramin 6.5 ± 3.2 sperm/egg (36 eggs) + 10 μM Suramin 3.8 ± 2.3 sperm/egg (43 eggs) + 100 μM Suramin 1.0 ± 0.8 sperm/egg (32 eggs) No adverse effects were observed on sperm mobility at 1 to 10 μM. A slight decrease occurred at 100 μM. Conclusions. Suramin inhibits binding of mouse sperm to homologous eggs in vitro under conditions previously found to give > 90% fertilization. The IC50 is approximately 3.5 μM.
Examples 3-8
The compounds hereinbefore referenced (a) to (f) were tested by the procedure described in Example 1 and gave the results set forth in Table 1 below:
Toxicity data taken from "Inhibitions of HIV-Type 1 Reverse Transcriptase by Suramin-related compounds" (K.D. Jentsch et al. J. Gen. Virol (1987) 68, 2183-92) is also included. Briefly, this toxicity work measured the toxicity of the compounds by exposing MT4 cells, a human HTLV-1 bearing cell line, to differing concentrations of the compound under study. The lowest concentration which impaired cell growth (measured by thymidine incorporation) was given as a measure of toxicity. The results are given in Table 1 as Cell Impairing Growth Concentration.
TABLE 1
IC50(mm) Cell Impairing Growth
Example No. Reference Concn. (mg/ml )
3 (a) 22 50
4 (b) 40 500
5 (c) 12 50
6 (d) 10 50
7 (e) 10 50
8 (f) 19 -
9 (g( 56 500 Example 9. Anti-fertility tests
Example 2 was repeated using various concentrations of the following compounds:
Suramin (Compound (a))
Compound (f)
Comparisons (i) and (ii) - the Suramin - related compounds designated NF036 and NF226 respectively 1n the paper by Jentsch it ϋl referenced above.
The results are tabulated in Table 2 below as percentage binding of spermatozoa to the zona pellucida taking as 100% a control experiment with no active compound
Table 2
Cone, of Active % Binding
Compound (μM) (a) (b) (i) (ii)
0 100 100 100 100
25 12 140 - -
50 2 75 112 -
100 0 10 115 99
500 1 58
1000 0.1
The results show the enhanced binding effect of the compounds of formula I compared with sulphonated compounds having modifi ed formulae.

Claims

Cl aims
1. A method of contraception comprising administering to a mammal a non-toxic amount of a compound of formula I effective to prevent conception:
(ABCD)2En (I)
in which formula I:
A represents A1 or A2
Figure imgf000016_0001
Figure imgf000016_0002
B represents
(A)┄ NH · CO┄ (C) C represents C1 or C2
Figure imgf000016_0004
Figure imgf000016_0003
D represents D1, D2, D3, D4 or D5
D1 (C)┄ NH┄ (E)
Figure imgf000017_0002
Figure imgf000017_0003
Figure imgf000017_0004
Figure imgf000017_0005
E represents E1, E2 or E3
/ K
Figure imgf000017_0001
M represents hydrogen or an alkali metal;
a + b = 1;
the dotted lines represent linkages to neighbouring groups shown in brackets;
c + d = o or l; e + f + g + h = o or l; R represents an alkyl group and
n = o or l .
2. A method of contraception according to claim 1 wherein the compound of formula I is a sodium salt.
3. A method of contraception according to claim 1 or 2 wherein A in the compound of formula I is A1.
4. A method of contraception according to claim 1, 2 or 3 wherein E in the compound of formula 1 is E1 and n is 1.
5. A method of contraception according to claim 1 wherein the compound of formula I has A = A1, a = 1, b = o, M = Na, C = C2, R = CH3, e + f + g = o, h = 1, R = CH3, D = D4, E = E1
6. A method of contraception according to claim 1 wherein the compound of formula I has A = A1, a = o, b = 1, M = Na, C = C1, c + d = o, D = D1, E = E1
7. A method of contraception according to claim 1 wherein the compound of formula I has A = A1, a = o, b = 1, M = Na, C = C1 · c + d = o, D = D2, E = E1
8. A method of contraception according to claim 1 wherein the compound of formula I has A = A1, a = 1, b = o, M = Na, C = C2, e + f + g + h = o, D = D3, E = E1
9. A method of contraception according to claim 1 wherein the compound of formula I has A = A1, a =1 , b = 0, M = Na, C = C2, e + f + g = 0, h = 1, R= CH3, D = D4, E = E3
10. A Method of contraception according to claim 1 wherein the compound of formula I has (f) A = A2, M = Na, C = C2,
e + f + g = o, h = 1, R = CH3, D = D4, E = E1 11. A method of contraception according to Claim 1 wherein the compound of formula I has A = A-|, a = 1 , b = o, M = Na, C = C2, e + f + g + h = o, D = D5, E = E1,
12. For use in the preparation of a contraceptive formulation a compound of formula I as defined in any one of claims 1 to 11.
PCT/GB1992/001925 1991-10-23 1992-10-20 Use of suramine and related compounds as contraceptive agents WO1993007864A1 (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB919122477A GB9122477D0 (en) 1991-10-23 1991-10-23 Contraceptive compounds
GB9122477.4 1991-10-23
GB9124789.0 1991-11-21
GB919124789A GB9124789D0 (en) 1991-11-21 1991-11-21 Contraceptive compounds

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5795860A (en) * 1993-03-01 1998-08-18 Repligen Corporation Analogs for specific oligosaccharide-protein interactions and uses therefor
WO2000058277A1 (en) * 1999-03-31 2000-10-05 American Home Products Corporation Aryl sulfonic acids and derivatives as fsh antagonists
WO2000058276A1 (en) * 1999-03-31 2000-10-05 American Home Products Corporation 7-amino-4-hydroxy-3-(4-methoxy-phenylazo)-naphthalene-2-sulfonic acid derivatives as fsh antagonists
US6200963B1 (en) 1999-03-31 2001-03-13 American Home Products Corporation Aryl sulfonic acids as FSH antagonists
US6355633B1 (en) 1999-03-31 2002-03-12 American Home Products Corporation Aryl sulfonic acids and derivatives as FSH antagonists
US20130029930A1 (en) * 2009-12-14 2013-01-31 Cornell University Activation and activators of sirt6
US8552064B2 (en) 2002-03-26 2013-10-08 Eastern Virginia Medical School Suramin and derivatives thereof as topical microbicide and contraceptive

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US4264575A (en) * 1979-07-16 1981-04-28 Eli Lilly And Company Contraceptive methods and compositions
EP0205077A2 (en) * 1985-06-11 1986-12-17 Bayer Ag Suramin sodium for use as an immunostimulant
DE3824669A1 (en) * 1988-07-20 1990-01-25 Wondrak Ewald M Composition for preventing infection with HIV
EP0381303A1 (en) * 1989-01-20 1990-08-08 EnTec Gesellschaft für endokrinologische Technologie m.b.H. Use of suramine and physiologically acceptable derivatives thereof, possibly in combination with anti-androgenic agents, for the preparation of a medicament for the treatment of human prostate carcinomia

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EP0355245A1 (en) * 1988-08-26 1990-02-28 Michel Vandevelde Use of retrovirus reverse transcriptase inhibiting agents

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US4264575A (en) * 1979-07-16 1981-04-28 Eli Lilly And Company Contraceptive methods and compositions
EP0205077A2 (en) * 1985-06-11 1986-12-17 Bayer Ag Suramin sodium for use as an immunostimulant
DE3824669A1 (en) * 1988-07-20 1990-01-25 Wondrak Ewald M Composition for preventing infection with HIV
EP0381303A1 (en) * 1989-01-20 1990-08-08 EnTec Gesellschaft für endokrinologische Technologie m.b.H. Use of suramine and physiologically acceptable derivatives thereof, possibly in combination with anti-androgenic agents, for the preparation of a medicament for the treatment of human prostate carcinomia

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Title
DEVELOPMENT vol. 111, no. 4, April 1991, pages 1155 - 1163 R. JONES 'INTERACTION OF ZONA PELLUCIDA GLYCOPROTEINS, SULPHATED CARBOHYDRATES AND SYNTHETIC POLYMERS WITH PROACROSIN, THE PUTATIVE EGG-BINDING PROTEIN FROM MAMMALIAN SPERMATOZOA' cited in the application *
JOURNAL OF REPRODUCTION & FERTILITY vol. 52, no. 2, 1978, pages 327 - 332 J.C. BOURSNELL ET AL. 'EFFECT OF EGG YOLK AND OTHER REAGENTS UPON THE ZINC OF COLD-SHOCKED BOAR SPERMATOZOA' *
THE JOURNAL OF GENERAL VIROLOGY vol. 68, no. 8, 1987, pages 2183 - 2192 K.D. JENTSCH ET AL. 'INHIBITION OF HUMAN IMMUNODEFICIENCY VIRUS TYPE I REVERSE TRANSCRIPTASE BY SURAMIN-RELATED COMPOUNDS' cited in the application *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5795860A (en) * 1993-03-01 1998-08-18 Repligen Corporation Analogs for specific oligosaccharide-protein interactions and uses therefor
WO2000058277A1 (en) * 1999-03-31 2000-10-05 American Home Products Corporation Aryl sulfonic acids and derivatives as fsh antagonists
WO2000058276A1 (en) * 1999-03-31 2000-10-05 American Home Products Corporation 7-amino-4-hydroxy-3-(4-methoxy-phenylazo)-naphthalene-2-sulfonic acid derivatives as fsh antagonists
US6200963B1 (en) 1999-03-31 2001-03-13 American Home Products Corporation Aryl sulfonic acids as FSH antagonists
US6355633B1 (en) 1999-03-31 2002-03-12 American Home Products Corporation Aryl sulfonic acids and derivatives as FSH antagonists
US8552064B2 (en) 2002-03-26 2013-10-08 Eastern Virginia Medical School Suramin and derivatives thereof as topical microbicide and contraceptive
US20130029930A1 (en) * 2009-12-14 2013-01-31 Cornell University Activation and activators of sirt6
US9322049B2 (en) * 2009-12-14 2016-04-26 Cornell University Activation and activators of SirT6

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