Substituted 4-phenylpiperidines, their preparation and use
Inventors
Petrukhin, Konstantin • Johnson, Graham • Allikmets, Rando • Cioffi, Christopher • FREEMAN, Emily • Chen, Ping • Conlon, Michael • Zhu, Lei
Assignees
Columbia University in the City of New York
Publication Number
US-12404277-B2
Publication Date
2025-09-02
Expiration Date
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Abstract
The present invention provides a compound having the structure:whereinR1, R2, R3, R4, and R5 are each independently H, halogen, CF3 or C1-C4 alkyl, wherein two or more of R1, R2, R3, R4, or R5 are other than H; R6 is H, OH, or halogen; andB is a substituted or unsubstituted heterobicycle,wherein when R1 is CF3, R2 is H, R3 is F, R4 is H, and R5 is H, or R1 is H, R2 is CF3, R3 is H, R4 is CF3, and R5 is H, or R1 is Cl, R2 is H, R3 is H, R4 is F, and R5 is H, or R1 is CF3, R2 is H, R3 is F, R4 is H, and R5 is H, or R1 is CF3, R2 is F, R3 is H, R4 is H, and R5 is H, or R1 is Cl, R2 is F, R3 is H, R4 is H, and R5 is H, then B is other than or a pharmaceutically acceptable salt thereof.
Core Innovation
The present invention provides a compound having the structure: wherein R1, R2, R3, R4, and R5 are each independently H, halogen, CF3 or C1-C4 alkyl, wherein two or more of R1, R2, R3, R4, or R5 are other than H; R6 is H, OH, or halogen; and B is a substituted or unsubstituted heterobicycle, wherein when R1 is CF3, R2 is H, R3 is F, R4 is H, and R5 is H, or R1 is H, R2 is CF3, R3 is H, R4 is CF3, and R5 is H, or R1 is Cl, R2 is H, R3 is H, R4 is F, and R5 is H, or R1 is CF3, R2 is H, R3 is F, R4 is H, and R5 is H, or R1 is CF3, R2 is F, R3 is H, R4 is H, and R5 is H, or R1 is Cl, R2 is F, R3 is H, R4 is H, and R5 is H, then B is other than or a pharmaceutically acceptable salt thereof.
Age-related macular degeneration (AMD) is the leading cause of blindness in developed countries and there is currently no FDA-approved treatment for dry AMD. Experimental and clinical data indicate that excessive accumulation of cytotoxic autofluorescent lipid-protein-retinoid aggregates (lipofuscin) in the retinal pigment epithelium (RPE) is a major trigger of dry AMD, and the major cytotoxic component of RPE lipofuscin is pyridinium bisretinoid A2E. As cytotoxic bisretinoids are formed during the course of a normally functioning visual cycle, the present invention provides compounds and related pharmaceutical compositions and methods for treating diseases characterized by excessive lipofuscin accumulation in the retina by employing the disclosed compounds, pharmaceutical compositions and methods of administration.
Claims Coverage
The patent includes two principal independent claims directed to methods that use the disclosed compound structures: one directed to inhibiting formation of an RBP4-retinol complex and one directed to inhibiting an RBP4/transthyretin (TTR) interaction. The inventive features center on contacting RBP4 with a compound having the recited substituted 4-phenylpiperidine structure and specified R substituents and heterobicycle B definitions.
Inhibiting formation of a retinol binding protein 4 (RBP4)-retinol complex
Contacting the RBP4 with a compound having the structure: wherein R1, R2, R3, R4, and R5 are each independently H, halogen, CF3 or C1-C4 alkyl, wherein two or more of R1, R2, R3, R4, or R5 are other than H; R6 is H, OH, or halogen; and B is a substituted or unsubstituted heterobicycle, wherein when R1 is CF3, R2 is H, R3 is F, R4 is H, and R5 is H, or R1 is H, R2 is CF3, R3 is H, R4 is CF3, and R5 is H, or R1 is Cl, R2 is H, R3 is H, R4 is F, and R5 is H, or R1 is CF3, R2 is H, R3 is F, R4 is H, and R5 is H, or R1 is CF3, R2 is F, R3 is H, R4 is H, and R5 is H, or R1 is Cl, R2 is F, R3 is H, R4 is H, and R5 is H, then B is other than or a pharmaceutically acceptable salt thereof.
Inhibiting a retinol binding protein 4 (RBP4)/transthyretin (TTR) interaction
Contacting the RBP4 with a compound having the structure: wherein R7 and R6 options and B heterobicycle choices are recited in corresponding dependent claim language, and wherein embodiments specify R7 is H and R6 is H, or further define B and R9 substituents as set forth in the specification and claim dependent recitations.
The independent claims are directed to methods of (1) inhibiting formation of an RBP4-retinol complex and (2) inhibiting an RBP4/TTR interaction by contacting RBP4 with the disclosed substituted 4-phenylpiperidine compounds defined by the recited R1–R6, R7/R9 options and heterobicycle B definitions; dependent claims further specify embodiments including in vivo and human contacting, and displacing retinol from RBP4.
Stated Advantages
Significantly increases the potency and improves pharmacokinetic characteristics of the molecules (for compounds comprising a 3,4-difluoro-2-(trifluoromethyl)phenyl moiety).
Significantly increases the potency and improves pharmacokinetic characteristics of the molecules (for compounds comprising a 3,5-difluoro-2-(trifluoromethyl)phenyl moiety).
Significantly increases the potency and improves pharmacokinetic characteristics of the molecules (for compounds comprising di- or trisubstituted phenyl moiety).
An amount of the compound can be effective to lower the serum concentration of RBP4 in the subject.
An amount of the compound can be effective to lower the retinal concentration of a bisretinoid in lipofuscin in the subject (for example A2E, isoA2E, A2-DHP-PE, atRAL di-PE).
Documented Applications
A method for treating a disease characterized by excessive lipofuscin accumulation in the retina in a subject comprising administering to the subject an effective amount of any one of the disclosed compounds or a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier.
Treatment of bisretinoid-mediated macular degeneration, including Age-Related Macular Degeneration or Stargardt Disease.
Treatment of Age-Related Macular Degeneration, including dry (atrophic) Age-Related Macular Degeneration.
Treatment of Stargardt Disease.
Treatment of Best disease.
Treatment of adult vitelliform maculopathy.
Treatment of Stargardt-like macular dystrophy.
Use as a pharmaceutical composition comprising any one of the compounds and a pharmaceutically acceptable carrier for administration to a mammal, including humans.
Use to lower serum RBP4 and to reduce formation or accumulation of retinal bisretinoids (such as A2E, isoA2E, A2-DHP-PE, atRAL di-PE) in the retina.
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