Method to treat psoriasis and other hyperproliferative skin disorders
Soluble adenylyl cyclase (sAC) is implicated in proliferation of keratinocytes. Inhibitors of sAC are useful for the treatment and/or prevention of psoriasis and other hyperproliferative skin disorders. Assays to identify such compounds are also described.
1. A method to inhibit hyperproliferative keratinocyte replication in a mammalian subject in need thereof, comprising:
administering to the subject a composition that inhibits soluble adenylyl cyclase in said mammalian keratinocyte, wherein the composition comprises a small molecule selected from the group consisting of Gossypol, 4-hydroxyestradiol, 2-hydroxyestradiol, 2-hydroxyestrone, 2-benzimidazolylthioacetamide-N-ethyl-2-benzyl (KH7.102), the compound of formula I (KH1)
the compound of formula II (KH2)
the compound of formula III (KH3)
the compound of formula IV (KH4)
the compound of formula V (KH8)
the compound of formula VI (KH7.120)
and a compound of formula VII
wherein R 1 and R 3 are each independently H or a C 1-4 alkyl
R 2 is a C 6-8 aryl, naphthalene or a C 4-5 heteroaryl having at least one hetero atom selected from N, S and O, the phenyl or C 4-5 heteroaryl optionally substituted with one or more radicals selected from the group consisting of hydroxyl, halogen, nitro, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 carboxyl, phenyl, C 1-4 alkoxy phenyl, and a halogenated C 1-4 alkyl, and
R 4 is H, a C 1-4 alkyl, a C 1-4 carboxyl or a C 6-8 aryl, optionally substituted with a C 1-4 alkyl, a C 1-4 alkoxy, hydroxyl or a halogen.
2. The method according to claim 1 , wherein the C 6-8 aryl is a phenyl or the C 4-6 heteroaryl is a pyridine, furan, or thiophene.
3. The method according to claim 1 , wherein the small molecule is selected from the group of compounds consisting of Gossypol, 4-hydroxyestradiol, 2-hydroxyestradiol, 2-hydroxyestrone, 2-benzimidazolylthioacetamide-N-ethyl-2-benzyl (KH7.102),
4. The method according to claim 1 , wherein the mammal is a human.
5. The method according to claim 1 , wherein the composition is administered topically, systemically, injected intradermally, or injected epidermally.