Management of ophthalmologic disorders, including macular degeneration

A compound of formula I:

• wherein, independently for each occurrence,
• n is 0 to 10 inclusive;
• R1 is hydrogen or alkyl;
• R2 is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, or aralkyl;
• Y is —C(Rb)p—, —C(═O)— or —C(Rb)pC(═O)—;
• X is —O—, —N(Ra)—, —C(Rb)p— or —S—;
• Z is alkyl, haloalkyl, —(CH2CH2O)pRb or —C(═O)Rb;
• p is 0 to 20 inclusive;
• Ra is hydrogen, alkyl, aryl or aralkyl;
• Rb is hydrogen, alkyl or haloalkyl;
• and
• denotes a single bond, a cis double bond, or a trans double bond;
• or
• a compound of formula II:
• wherein, independently for each occurrence,
• n is 0 to 10 inclusive;
• R1 is hydrogen or alkyl;
• R2 is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, or aralkyl;
• Y is —C(Rb)p—, —C(═O)— or —C(Rb)pC(═O)—;
• X is hydrogen, —O—, —S—, —N(Ra)—, —N(Ra)—N(Ra)—, —C(═O)—, —C(═NRa)—, —C(═NOH)—, —C(═S)— or —C(Rb)p—;
• Z is absent, hydrogen, alkyl, haloalkyl, aryl, aralkyl, —CN, —ORb, —(CH2CH2O)pRb, —C(═O)Rb, —C(═O)CH2F, —C(═O)CHF2, —C(═O)CF3, —C(═O)CHN2, —C(═O)ORb, —C(═O)CH2OC(═O)Rb, —C(═O)C(═C(Rb)2, Rb,
• p is 0 to 20 inclusive;
• Ra is hydrogen, alkyl, aryl or aralkyl,
• Rb is hydrogen, alkyl, haloalkyl, aryl or aralkyl;
• and
• denotes a single bond, a cis double bond or a trans double bond;
• or
• a compound of formula III:
• wherein
• n is 0 to 10 inclusive,
• R1 is hydrogen or alkyl;
• R2 is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, or aralkyl;
• Y is —CRb(ORb)—, —CRb(N(Ra)2)—, —C(Rb)p—, —C(═O)— or —C(Rb)pC(═O)—;
• X is —O—, —S—, —N(Ra)—, —C(═O)—, or —C(Rb)p—;
• Z is hydrogen, alkyl, haloalkyl, aryl, aralkyl, —ORb, —N(Rb)2, —(CH2CH2O)pRb, —C(═O)Rb, —C(═NRa)Rb, —C(═NORb)Rb, —C(ORb)(Rb)2, —C(N(Ra)2)(Rb)2 or —(CH2CH2O)pRb;
• p is 0 to 20 inclusive;
• Ra is hydrogen, alkyl, aryl or aralkyl;
• Rb is hydrogen, alkyl, haloalkyl, aryl or aralkyl;
• and
• denotes a single bond or a trans double bond.

A compound of formula IV:

• wherein, independently for each occurrence,
• n is 1, 2, 3 or 4;
• Y is —C(Rb)2— or —C(═O)—;
• X is —O—, —NRa—, —C(Rb)2— or —C(═O)—;
• Z is —C(═O)Rb, —ORb, —N(Rb)2, alkyl or haloalkyl;
• Ra is hydrogen, alkyl, haloalkyl, aryl or aralkyl;
• and
• Rb is hydrogen, alkyl, haloalkyl, aryl or aralkyl;
• or
• a compound of formula V:
• wherein, independently for each occurrence,
• n is 1, 2 or 3;
• Y is —C(Rb)2—, —C(═O)— or —CH(OH)—;
• X is —O—, —NRa— or —C(Rb)2—;
• Z is —C(═O)Rb, hydrogen, —(CH2CH2O)pRb, alkyl or haloalkyl;
• Ra is hydrogen, alkyl, haloalkyl, aryl or aralkyl;
• Rb is hydrogen, alkyl, haloalkyl, aryl or aralkyl;
• and
• p is 1 to 10 inclusive;
• or
• a compound of formula VI:
• wherein, independently for each occurrence,
• R1 is hydrogen, alkyl, aryl or aralkyl;
• X is alkyl, alkenyl, —C(Rb)2—, —C(═O)—, —C(═NRa)—, —C(OH)Rb or —C(N(Ra)2)Rb—;
• R2 is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, or aralkyl;
• Ra is hydrogen, alkyl, aryl or aralkyl;
• and
• Rb is hydrogen or alkyl;
• or
• a compound of formula VII:
• wherein, independently for each occurrence:
• R is H, alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or carbonyl;
• L is a hydrophobic moiety, or any two adjacent L taken together form a fused aromatic or heteroaromatic ring.

A compound of formula VIII:

• wherein R′ is hydrogen, alkyl or ether;
• or any two adjacent L taken together form a fused aromatic or heteroaromatic ring;
• or
• a compound of formula IX:
• ANR2 IX
• wherein, independently for each occurrence:
• R is H, alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or carbonyl;
• and
• A is optionally substituted aryl or heteroaryl;
• or
• a compound of formula X:
• AC(═O)NHNH2 X
• wherein independently for each occurrence:
• R′ is hydrogen, alkyl or ether;
• and
• A is optionally substituted aryl or heteroaryl;
• or
• a compound of formula XI:
• wherein, independently for each occurrence,
• n is 0 to 10 inclusive,
• R1 is hydrogen or alkyl,
• R2 is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, or aralkyl;
• Z is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, aralkyl, —C(═O)Rb, or —(CH2)pRb;
• p is 0 to 20 inclusive;
• Ra is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, or aralkyl;
• Rb is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, or aralkyl;
• and
• denotes a single bond or a trans double bond.

The compound of claim 254, wherein said compound is represented by formula XIa:

• wherein, independently for each occurrence,
• n is 0 to 10 inclusive;
• R1 is hydrogen or alkyl;
• R2 is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, or aralkyl;
• R3, R4, R5, R6 and R7 are hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, aralkyenyl, aralkynyl, heteroaralkyl, heteroaralkyenyl, heteroaralkynyl, cyano, nitro, sulfhydryl, hydroxyl, sulfonyl, amino, acylamino, amido, alkylthio, carboxyl, carbamoyl, alkoxyl, sulfonate, sulfate, sulfonamido, sulfamoyl, sulfonyl, or sulfoxido;
• Ra is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, or aralkyl;
• and
• denotes a single bond or a trans double bond.

The compound of claim 254, wherein said compound is represented by formula XIb:

• wherein, independently for each occurrence,
• n is 0 to 5 inclusive;
• R1 is hydrogen or methyl;
• R2 is hydrogen, alkyl, alkenyl, alkynyl, aryl,
• R3, R4, R5, R6, R7 and R8 are hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, aralkyenyl, aralkynyl, heteroaralkyl, heteroaralkyenyl, heteroaralkynyl, cyano, nitro, sulfhydryl, hydroxyl, sulfonyl, amino, acylamino, amido, alkylthio, carboxyl, carbamoyl, alkoxyl, sulfonate, sulfate, sulfonamido, sulfamoyl, sulfonyl, or sulfoxido;
• any two geminal R8 and the carbon to which they are bound may represent C(═O);
• and
• Ra is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, or aralkyl.

A method of identifying a drug for treating or preventing an ophthalmologic disorder, comprising:

• administering a candidate drug to a subject having, or at risk for developing, the ophthalmologic disorder;
• and
• measuring accumulation of a retinotoxic compound in the retinal pigment epithelium (RPE) of the subject;
• wherein accumulation of the retinotoxic compound in the RPE in the presence of the candidate drug relative to the absence of the candidate drug indicates that the candidate drug is a drug for treating or preventing the ophthalmologic disorder.

A method of identifying a drug for treating or preventing an ophthalmologic disorder, comprising:

• contacting one or more cells representing an in vitro model of the visual cycle with the candidate drug;
• and
• measuring accumulation of a visual cycle intermediate product in at least one cell;
• wherein accumulation of the intermediate product in the presence of the candidate drug relative to the absence of the candidate drug indicates that the candidate drug is a drug for treating or preventing the ophthalmologic disorder.