Oligopyrroles as antagonists of islet amyloid polypeptide oligomerization

A method of altering the structure of an amyloidogenic peptide comprising contacting said peptide with an effective amount of the compound of formula (I):

• wherein Ra is independently selected at each occurrence from hydrogen, C1-C12 hydrocarbons, —F;
• —Cl;
• —Br;
• —I;
• —OH, —OR*;
• —SO3H;
• —NO;
• —NO2;
• —NO3;
• —O—NO;
• —N3;
• —NH2;
• —NHR*;
• and —N(R*)2;
• X is independently at each occurrence selected from —O—;
• —S—;
• —NH—;
• —NR*—;
• and —C(R*)2;
• R1 is selected from hydrogen or a straight chained, branched or cyclic aliphatic C1-C20 hydrocarbon;
• an aromatic C6-C20 hydrocarbon;
• a heteroaromatic C1-C20 hydrocarbon;
• an aryl C6-C20 hydrocarbon;
• a heteroaryl C1-C20 hydrocarbon, a C1-C12 perfluorocarbon, or a combination thereof, each of which optionally contains 1-8 heteroatoms selected from halogen, O, N, and S, and each of which is optionally substituted with one or more of —F;
• —Cl;
• —Br;
• —I;
• —OH, —OR*;
• —NO;
• —NO2;
• —NO3;
• —O—NO;
• —N3;
• —NH2;
• —NHR*;
• —N(R*)2;
• —N(R*)3+;
• —N(R*)—OH;
• —O—N(R*)2;
• —N(R*)—O—R*;
• —CN;
• —NC;
• —(C═O)—R*;
• —CHO;
• —CO2H;
• —CO2R*;
• —(C═O)—S—R*;
• —O—(C═O)—H;
• —O—(C═O)—R*;
• —S—(C═O)—R*;
• —(C═O)—NH2;
• —(C═O)—N(R*)2;
• —(C═O)—NHNH2;
• —O—(C═O)—NHNH2;
• —(C═S)—NH2;
• —(C═S)—N(R*)2;
• —N(R*)—CHO;
• —N(R*)—(C═O)—R*;
• —SCN;
• —NCS;
• —NSO;
• —SSR*;
• —SO2R*;
• —SO3H;
• —SO2—N(R*)2;
• —S(═O)—OR*;
• —S(═O)—R*;
• —Si(R*)3;
• —CF3;
• —O—CF3;
• —P(R*)2;
• —O—P(═O)(OR*)2;
• —P(═O)(OR*)2 and combinations thereof;
• R2 is independently at each occurrence selected from hydrogen or a straight chained, branched or cyclic aliphatic C1-C20 hydrocarbon;
• an aromatic C6-C20 hydrocarbon;
• a heteroaromatic C1-C20 hydrocarbon;
• an aryl C6-C20 hydrocarbon;
• a heteroaryl C1-C20 hydrocarbon, a C1-C12 perfluorocarbon, or a combination thereof, each of which optionally contains 1-8 heteroatoms selected from halogen, O, N, and S, and each of which is optionally substituted with one or more of —F;
• —Cl;
• —Br;
• —I;
• —OH, —OR*;
• —NO;
• —NO2;
• —NO3;
• —O—NO;
• —N3;
• —NH2;
• —NHR*;
• —N(R*)2;
• —N(R*)3+;
• —N(R*)—OH;
• —O—N(R*)2;
• —N(R*)—O—R*;
• —CN;
• —NC;
• —(C═O)—R*;
• —CHO;
• —CO2H;
• —CO2R*;
• —(C═O)—S—R*;
• —O—(C═O)—H;
• —O—(C═O)—R*;
• —S—(C═O)—R*;
• —(C═O)—NH2;
• —(C═O)—N(R*)2;
• —(C═O)—NHNH2;
• —O—(C═O)—NHNH2;
• —(C═S)—NH2;
• —(C═S)—N(R*)2;
• —N(R*)—CHO;
• —N(R*)—(C═O)—R*;
• —SCN;
• —NCS;
• —NSO;
• —SSR*;
• —SO2R*;
• —SO3H;
• —SO2—N(R*)2;
• —S(═O)—OR*;
• —S(═O)—R*;
• —Si(R*)3;
• —CF3;
• —O—CF3;
• —P(R*)2;
• —O—P(═O)(OR*)2;
• —P(═O)(OR*)2 and combinations thereof;
• R3 is selected from hydrogen or a straight chained, branched or cyclic aliphatic C1-C20 hydrocarbon;
• an aromatic C6-C20 hydrocarbon;
• a heteroaromatic C1-C20 hydrocarbon;
• an aryl C6-C20 hydrocarbon;
• a heteroaryl C1-C20 hydrocarbon, a C1-C12 perfluorocarbon, or a combination thereof, each of which optionally contains 1-8 heteroatoms selected from halogen, O, N, and S, and each of which is optionally substituted with one or more of —F;
• —Cl;
• —Br;
• —I;
• —OH, —OR*;
• —NO;
• —NO2;
• —NO3;
• —O—NO;
• —N3;
• —NH2;
• —NHR*;
• —N(R*)2;
• —N(R*)3+;
• —N(R*)—OH;
• —O—N(R*)2;
• —N(R*)—O—R*;
• —CN;
• —NC;
• —(C═O)—R*;
• —CHO;
• —CO2H;
• —CO2R*;
• —(C═O)—S—R*;
• —O—(C═O)—H;
• —O—(C═O)—R*;
• —S—(C═O)—R*;
• —(C═O)—NH2;
• —(C═O)—N(R*)2;
• —(C═O)—NHNH2;
• —O—(C═O)—NHNH2;
• —(C═S)—NH2;
• —(C═S)—N(R*)2;
• —N(R*)—CHO;
• —N(R*)—(C═O)—R*;
• —SCN;
• —NCS;
• —NSO;
• —SSR*;
• —SO2R*;
• —SO3H;
• —SO2—N(R*)2;
• —S(═O)—OR*;
• —S(═O)—R*;
• —Si(R*)3;
• —CF3;
• —O—CF3;
• —P(R*)2;
• —O—P(═O)(OR*)2;
• —P(═O)(OR*)2 and combinations thereof;
• A is selected from hydrogen, —F;
• —Cl;
• —Br;
• —I;
• —OH, —OR*;
• —NO;
• —NO2;
• —NO3;
• —O—NO;
• —N3;
• —NH2;
• NHR*, N(R*)2;
• —N(R*)—OH;
• —O—N(R*)2;
• —N(R*)—O—R*;
• —CN;
• —NC;
• —(C═O)—R*;
• —CHO;
• —CO2H;
• —CO2R*;
• —(C═O)—S—R*;
• —O—(C═O)—H;
• —O—(C═O)—R*;
• —S—(C═O)—R*;
• —(C═O)—NH2;
• —(C═O)—N(R*)2;
• —(C═O)—NHNH2;
• —(C═O)—NHR*;
• —O—(C═O)—NHNH2;
• —(C═S)—NH2;
• —(C═S)—N(R*)2;
• —N(R*)—CHO;
• —N(R*)—(C═O)—R*;
• —SCN;
• —NCS;
• —NSO;
• —SSR*;
• —SO2R*;
• —SO3H;
• —SO2—N(R*)2;
• —S(═O)—OR*;
• —S(═O)—R*;
• —Si(R*)3;
• —CF3;
• —O—CF3;
• —P(R*)2;
• —O—P(═O)(OR*)2;
• —P(═O)(OR*)2;
• C1-C8 perfluorocarbon;
• an aliphatic C1-C12 hydrocarbon;
• an aromatic C1-C12 hydrocarbon;
• and a C1-C12 heteroaryl;
• B is selected from hydrogen, —F;
• —Cl;
• —Br;
• —I;
• —OH, —OR*;
• —NO;
• —NO2;
• —NO3;
• —O—NO;
• —N3;
• —NH2;
• —NHR*;
• —N(R*)2;
• —N(R*)3+;
• —N(R*)—OH;
• —O—N(R*)2;
• —N(R*)—O—R*;
• —CN;
• —NC;
• —(C═O)—R*;
• —CHO;
• —CO2H;
• —CO2R*;
• —(C═O)—S—R*;
• —O—(C═O)—H;
• —O—(C═O)—R*;
• —S—(C═O)—R*;
• —(C═O)—NH2;
• —(C═O)—NHR*;
• —(C═O)—N(R*)2;
• —(C═O)—NHNH2;
• —O—(C═O)—NHNH2;
• —(C═S)—NH2;
• —(C═S)—N(R*)2;
• —N(R*)—CHO;
• —N(R*)—(C═O)—R*;
• —SCN;
• —NCS;
• —NSO;
• —SSR*;
• —SO2R*;
• —SO3H;
• —SO2—N(R*)2;
• —S(═O)—OR*;
• —S(═O)—R*;
• —Si(R*)3;
• —CF3;
• —O—CF3;
• —P(R*)2;
• —O—P(═O)(OR*)2;
• —P(═O)(OR*)2;
• C1-C8 perfluorocarbon;
• an aliphatic C1-C12 hydrocarbon;
• an aromatic C1-C12 hydrocarbon;
• and a C1-C12 heteroaryl;
• R* is independently selected at each occurrence from hydrogen or C1-C12 hydrocarbons each of which optionally contains 1-8 heteroatoms selected from halogen, O, N, and S and combinations thereof;
• and
• n is 0 or 1,
• or a pharmaceutically acceptable salt thereof.

A method of modulating oligomerization of an amyloidogenic peptide comprising contacting said peptide with an effective amount of the compound of formula (I):

• wherein Ra is independently selected at each occurrence from hydrogen, C1-C12 hydrocarbons, —F;
• —Cl;
• —Br;
• —I;
• —OH, —OR*;
• —SO3H;
• —NO;
• —NO2;
• —NO3;
• —O—NO;
• —N3;
• —NH2;
• —NHR*;
• and —N(R*)2;
• X is independently at each occurrence selected from —O—;
• —S—;
• —NH—;
• —NR*—;
• and —C(R*)2;
• R1 is selected from hydrogen or a straight chained, branched or cyclic aliphatic C1-C20 hydrocarbon;
• an aromatic C6-C20 hydrocarbon;
• a heteroaromatic C1-C20 hydrocarbon;
• an aryl C6-C20 hydrocarbon;
• a heteroaryl C1-C20 hydrocarbon, a C1-C12 perfluorocarbon, or a combination thereof, each of which optionally contains 1-8 heteroatoms selected from halogen, O, N, and S, and each of which is optionally substituted with one or more of —F;
• —Cl;
• —Br;
• —I;
• —OH, —OR*;
• —NO;
• —NO2;
• —NO3;
• —O—NO;
• —N3;
• —NH2;
• —NHR*;
• —N(R*)2;
• —N(R*)3+;
• —N(R*)—OH;
• —O—N(R*)2;
• —N(R*)—O—R*;
• —CN;
• —NC;
• —(C═O)—R*;
• —CHO;
• —CO2H;
• —CO2R*;
• —(C═O)—S—R*;
• —O—(C═O)—H;
• —O—(C═O)—R*;
• —S—(C═O)—R*;
• —(C═O)—NH2;
• —(C═O)—N(R*)2;
• —(C═O)—NHNH2;
• —O—(C═O)—NHNH2;
• —(C═S)—NH2;
• —(C═S)—N(R*)2;
• —N(R*)—CHO;
• —N(R*)—(C═O)—R*;
• —SCN;
• —NCS;
• —NSO;
• —SSR*;
• —SO2R*;
• —SO3H;
• —SO2—N(R*)2;
• —S(═O)—OR*;
• —S(═O)—R*;
• —Si(R*)3;
• —CF3;
• —O—CF3;
• —P(R*)2;
• —O—P(═O)(OR*)2;
• —P(═O)(OR*)2 and combinations thereof;
• R2 is independently at each occurrence selected from hydrogen or a straight chained, branched or cyclic aliphatic C1-C20 hydrocarbon;
• an aromatic C6-C20 hydrocarbon;
• a heteroaromatic C1-C20 hydrocarbon;
• an aryl C6-C20 hydrocarbon;
• a heteroaryl C1-C20 hydrocarbon, a C1-C12 perfluorocarbon, or a combination thereof, each of which optionally contains 1-8 heteroatoms selected from halogen, O, N, and S, and each of which is optionally substituted with one or more of —F;
• —Cl;
• —Br;
• —I;
• —OH, —OR*;
• —NO;
• —NO2;
• —NO3;
• —O—NO;
• —N3;
• —NH2;
• —NHR*;
• —N(R*)2;
• —N(R*)3+;
• —N(R*)—OH;
• —O—N(R*)2;
• —N(R*)—O—R*;
• —CN;
• —NC;
• —(C═O)—R*;
• —CHO;
• —CO2H;
• —CO2R*;
• —(C═O)—S—R*;
• —O—(C═O)—H;
• —O—(C═O)—R*;
• —S—(C═O)—R*;
• —(C═O)—NH2;
• —(C═O)—N(R*)2;
• —(C═O)—NHNH2;
• —O—(C═O)—NHNH2;
• —(C═S)—NH2;
• —(C═S)—N(R*)2;
• —N(R*)—CHO;
• —N(R*)—(C═O)—R*;
• —SCN;
• —NCS;
• —NSO;
• —SSR*;
• —SO2R*;
• —SO3H;
• —SO2—N(R*)2;
• —S(═O)—OR*;
• —S(═O)—R*;
• —Si(R*)3;
• —CF3;
• —O—CF3;
• —P(R*)2;
• —O—P(═O)(OR*)2;
• —P(═O)(OR*)2 and combinations thereof;
• R3 is selected from hydrogen or a straight chained, branched or cyclic aliphatic C1-C20 hydrocarbon;
• an aromatic C6-C20 hydrocarbon;
• a heteroaromatic C1-C20 hydrocarbon;
• an aryl C6-C20 hydrocarbon;
• a heteroaryl C1-C20 hydrocarbon, a C1-C12 perfluorocarbon, or a combination thereof, each of which optionally contains 1-8 heteroatoms selected from halogen, O, N, and S, and each of which is optionally substituted with one or more of —F;
• —Cl;
• —Br;
• —I;
• —OH, —OR*;
• —NO;
• —NO2;
• —NO3;
• —O—NO;
• —N3;
• —NH2;
• —NHR*;
• —N(R*)2;
• —N(R*)3+;
• —N(R*)—OH;
• —O—N(R*)2;
• —N(R*)—O—R*;
• —CN;
• —NC;
• —(C═O)—R*;
• —CHO;
• —CO2H;
• —CO2R*;
• —(C═O)—S—R*;
• —O—(C═O)—H;
• —O—(C═O)—R*;
• —S—(C═O)—R*;
• —(C═O)—NH2;
• —(C═O)—N(R*)2;
• —(C═O)—NHNH2;
• —O—(C═O)—NHNH2;
• —(C═S)—NH2;
• —(C═S)—N(R*)2;
• —N(R*)—CHO;
• —N(R*)—(C═O)—R*;
• —SCN;
• —NCS;
• —NSO;
• —SSR*;
• —SO2R*;
• —SO3H;
• —SO2—N(R*)2;
• —S(═O)—OR*;
• —S(═O)—R*;
• —Si(R*)3;
• —CF3;
• —O—CF3;
• —P(R*)2;
• —O—P(═O)(OR*)2;
• —P(═O)(OR*)2 and combinations thereof;
• A is selected from hydrogen, —F;
• —Cl;
• —Br;
• —I;
• —OH, —OR*;
• —NO;
• —NO2;
• —NO3;
• —O—NO;
• —N3;
• —NH2;
• NHR*, N(R*)2;
• —N(R*)—OH;
• —O—N(R*)2;
• —N(R*)—O—R*;
• —CN;
• —NC;
• —(C═O)—R*;
• —CHO;
• —CO2H;
• —CO2R*;
• —(C═O)—S—R*;
• —O—(C═O)—H;
• —O—(C═O)—R*;
• —S—(C═O)—R*;
• —(C═O)—NH2;
• —(C═O)—N(R*)2;
• —(C═O)—NHNH2;
• —(C═O)—NHR*;
• —O—(C═O)—NHNH2;
• —(C═S)—NH2;
• —(C═S)—N(R*)2;
• —N(R*)—CHO;
• —N(R*)—(C═O)—R*;
• —SCN;
• —NCS;
• —NSO;
• —SSR*;
• —SO2R*;
• —SO3H;
• —SO2—N(R*)2;
• —S(═O)—OR*;
• —S(═O)—R*;
• —Si(R*)3;
• —CF3;
• —O—CF3;
• —P(R*)2;
• —O—P(═O)(OR*)2;
• —P(═O)(OR*)2;
• C1-C8 perfluorocarbon;
• an aliphatic C1-C12 hydrocarbon;
• an aromatic C1-C12 hydrocarbon;
• and a C1-C12 heteroaryl;
• B is selected from hydrogen, —F;
• —Cl;
• —Br;
• —I;
• —OH, —OR*;
• —NO;
• —NO2;
• —NO3;
• —O—NO;
• —N3;
• —NH2;
• —NHR*;
• —N(R*)2;
• —N(R*)3+;
• —N(R*)—OH;
• —O—N(R*)2;
• —N(R*)—O—R*;
• —CN;
• —NC;
• —(C═O)—R*;
• —CHO;
• —CO2H;
• —CO2R*;
• —(C═O)—S—R*;
• —O—(C═O)—H;
• —O—(C═O)—R*;
• —S—(C═O)—R*;
• —(C═O)—NH2;
• —(C═O)—NHR*;
• —(C═O)—N(R*)2;
• —(C═O)—NHNH2;
• —O—(C═O)—NHNH2;
• —(C═S)—NH2;
• —(C═S)—N(R*)2;
• —N(R*)—CHO;
• —N(R*)—(C═O)—R*;
• —SCN;
• —NCS;
• —NSO;
• —SSR*;
• —SO2R*;
• —SO3H;
• —SO2—N(R*)2;
• —S(═O)—OR*;
• —S(═O)—R*;
• —Si(R*)3;
• —CF3;
• —O—CF3;
• —P(R*)2;
• —O—P(═O)(OR*)2;
• —P(═O)(OR*)2;
• C1-C8 perfluorocarbon;
• an aliphatic C1-C12 hydrocarbon;
• an aromatic C1-C12 hydrocarbon;
• and a C1-C12 heteroaryl;
• R* is independently selected at each occurrence from hydrogen or C1-C12 hydrocarbons each of which optionally contains 1-8 heteroatoms selected from halogen, O, N, and S and combinations thereof;
• and
• n is 0 or 1,
• or a pharmaceutically acceptable salt thereof.