- Evaluation of synthetic FK506 analogues as ligands for the FK506-binding proteins 51 and 52
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The FK506-binding proteins (FKBP) 51 and 52 are cochaperones that modulate the signal transduction of steroid hormone receptors. Both proteins have been implicated in prostate cancer. Furthermore, single nucleotide polymorphisms in the gene encoding FKBP51 have been associated with a variety of psychiatric disorders. Rapamycin and FK506 are two macrocyclic natural products that bind to these proteins indiscriminately but with nanomolar affinity. We here report the cocrystal structure of FKBP51 with a simplified α-ketoamide analogue derived from FK506 and the first structure-activity relationship analysis for FKBP51 and FKBP52 based on this compound. In particular, the tert-pentyl group of this ligand was systematically replaced by a cyclohexyl ring system, which more closely resembles the pyranose ring in the high-affinity ligands rapamycin and FK506. The interaction with FKBPs was found to be surprisingly tolerant to the stereochemistry of the attached cyclohexyl substituents. The molecular basis for this tolerance was elucidated by X-ray cocrystallography.
- Gopalakrishnan, Ranganath,Kozany, Christian,Gaali, Steffen,Kress, Christoph,Hoogeland, Bastiaan,Bracher, Andreas,Hausch, Felix
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supporting information; scheme or table
p. 4114 - 4122
(2012/06/30)
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- N-linked sulfonamide of heterocyclic thioesters for vision and memory disorders
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This invention relates to pharmaceutical compositions and methods for treating a vision disorder, improving vision, treating memory impairment, or enhancing memory performance using N-linked sulfonamides of heterocyclic thioesters.
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Page/Page column 29
(2008/12/07)
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- Carboxylic acids and carboxylic acid isosteres of N-heterocyclic compounds for vision and memory disorders
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This invention relates to novel compositions and uses of N-heterocyclic carboxylic acids and carboxylic acid isosteres for treating a vision disorder, improving vision, treating memory impairment or enhancing memory performance in an animal.
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Page/Page column 22-23; 25-26
(2008/06/13)
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- HETEROCYCLIC THIOESTER AND KETONE HAIR GROWTH COMPOSITIONS AND USES
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This invention relates to pharmaceutical compositions and methods for treating alopecia and promoting hair growth using heterocyclic thioesters and ketones.
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Page/Page column 19
(2010/11/23)
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- Method for treating nerve injury caused as a result of surgery
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The present invention relates generally to methods for treating or preventing nerve injury in a warm-blooded animal caused as a consequence of surgery by administering neurotrophic compounds described below. The invention relates more specifically to methods for treating or preventing nerve injury caused as a consequence of prostate surgery as well as erectile dysfunction.
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- N-linked urea or carbamate of heterocyclic thioesters for vision and memory disorders
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The present invention relates to pharmaceutical compositions comprising and methods of using an N-linked urea or carbamate of a heterocyclic thioester for treating a vision disorder, improving vision, treating memory impairment, or enhancing memory performance.
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- Synthesis of N-glyoxyl prolyl and pipecolyl amides and thioesters and evaluation of their in vitro and in vivo nerve regenerative effects
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The recent discovery that small molecule ligands for the peptidyl-prolyl isomerase (PPIase) FKBP12 possess powerful neuroprotective and neuroregenerative properties in vitro and in vivo suggests therapeutic utility for such compounds in neurodegenerative disease. The neurotrophic effects of these compounds are independent of the immunosuppressive pathways by which drugs such as FK506 and rapamycin operate. Previous work by ourselves and other groups exploring the structure-activity relationships (SAR) of small molecules that mimic only the FKBP binding domain portion of FK506 has focused on esters of proline and pipecolic acid. We have explored amide and thioester analogues of these earlier structures and found that they too are extremely potent in promoting recovery of lesioned dopaminergic pathways in a mouse model of Parkinson's disease. Several compounds were shown to be highly effective upon oral administration after lesioning of the dopaminergic pathway, providing further evidence of the potential clinical utility of a variety of structural classes of FKBP12 ligands.
- Hamilton, Gregory S.,Wu, Yong-Qian,Limburg, David C.,Wilkinson, Douglas E.,Vaal, Mark J.,Li, Jia-He,Thomas, Christine,Huang, Wei,Sauer, Hansjorg,Ross, Douglas T.,Soni, Raj,Chen, Yi,Guo, Hongshi,Howorth, Pamela,Valentine, Heather,Liang, Shi,Spicer, Dawn,Fuller, Mike,Steiner, Joseph P.
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p. 3549 - 3557
(2007/10/03)
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- Nitrogen-containing linear and azepinyl/ compositions and uses for vision and memory disorders
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This invention relates to pharmaceutical compositions and methods for treating a vision disorder, improving vision, treating memory impairment, or enhancing memory performance in an animal, using pipecolic acid derivatives.
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Page column 19
(2010/02/04)
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- N-oxide of heterocyclic ester, amide, thioester, or ketone hair growth compositions and uses
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This invention relates to pharmaceutical compositions and methods for treating alopecia and promoting hair growth using an N-oxide of a heterocyclic ester, amide, thioester, or ketone.
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- N-linked sulfonamides of N-heterocyclic carboxylic acids or isosteres for vision and memory disorders
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This invention relates to novel compositions and uses of a N-linked sulfonamide of an N-heterocylic carboxylic acid or isostere thereof for treating a vision disorder or improving vision or treating memory impairment or enhancing memory performance in an animal.
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- N-oxide of heterocyclic ester, amide, thioester, or ketone hair growth compositions and uses
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This invention relates to pharmaceutical compositions and methods for treating alopecia and promoting hair growth using an N-oxide of a heterocyclic ester, amide, thioester, or ketone.
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- Heterocyclic thioesters or ketones for vision and memory disorders
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This invention relates to pharmaceutical compositions and methods for treating a vision disorder, improving vision, treating memory impairment, or enhancing memory performance using heterocyclic thioesters and ketones.
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- Small molecule carbamates or ureas for vision and memory disorders
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This invention relates to pharmaceutical compositions and methods for treating a vision disorder, improving vision, treating memory impairment, or enhancing memory performance using small molecule carbamates and ureas.
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- Pipecolic acid derivatives for vision and memory disorders
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This invention relates to pharmaceutical compositions and methods for treating a vision disorder, improving vision, treating memory impairment, or enhancing memory performance using pipecolic acid derivatives.
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- Pyrrolidine derivative hair growth compositions and uses
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This invention relates to pharmaceutical compositions and methods for treating alopecia and promoting hair growth using pyrrolidine derivatives.
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- Pyrrolidine derivative hair growth compositions and uses
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This invention relates to pharmaceutical compositions and methods for treating alopecia and promoting hair growth using pyrrolidine derivatives.
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- Carboxylic acids and carboxylic acid isosteres of N-heterocyclic compounds
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This invention relates to novel N-heteorocyclic carboxylic acids and carboxylic acid isosteres, their preparation and use for treating neurological disorders including physically damaged nerves and neurodengenerative diseases, for treating alopecia and promoting hair growth, for treating vision disorders and/or improving vision, and for treating memory impairment and/or enhancing memory performance by administering such compounds.
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- Pyrrolidine derivatives for vision and memory disorders
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This invention relates to pharmaceutical compositions and methods for treating a vision disorder, improving vision, treating memory impairment, or enhancing memory performance using pyrrolidine derivatives.
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- Heterocyclic thioester and ketone hair growth compositions and uses
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This invention relates to pharmaceutical compositions and methods for treating alopecia and promoting hair growth using heterocyclic thioesters and ketones.
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- Heterocyclic ketone and thioester compounds and uses
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This invention relates to neurotrophic, low molecular weight, small molecule heterocyclic ketone and thioester compounds, compositions containing the same, and the use of such compounds for treating neurological disorders, including physically damaged nerves and neurodegenerative diseases.
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- N-oxide of heterocyclic ester, amide, thioester, or ketone hair growth compositions and uses
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This invention relates to pharmaceutical compositions and methods for treating alopecia and promoting hair growth using N-oxides of heterocyclic esters, amides, thioesters, or ketones.
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- Small molecule inhibitors of rotamase enzyme activity
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This invention relates to neurotrophic N-glyoxyl-prolyl ester compounds having an affinity for FKBP-type immunophilins, their preparation and use as inhibitors of the enzyme activity associated with immunophilin proteins, and particularly inhibitors of peptidyl-prolyl isomerase or rotamase enzyme activity.
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- Heterocyclic thioesters and ketones
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This invention relates to neurotrophic low molecular weight, small molecule heterocyclic thioesters and ketones having an affinity for FKBP-type immunophilins, and their use as inhibitors of the enzyme activity associated with immunophilin proteins, particularly peptidyl-prolyl isomerase, or rotamase, enzyme activity.
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- Heterocyclic thioesters
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This invention relates to neurotrophic low molecular weight, small molecule heterocyclic thioesters and ketones having an affinity for FKBP-type immunophilins, and their use as inhibitors of the enzyme activity associated with immunophilin proteins, particularly peptidyl-prolyl isomerase, or rotamase, enzyme activity.
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- N-oxides of heterocyclic esters, amides, thioesters, and ketones
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This invention relates to neurotrophic low molecular weight, small molecule N-oxides of heterocyclic esters, amides, thioesters, and ketones having an affinity for FKBP-type immunophilins, and their use as inhibitors of the enzyme activity associated with immunophilin proteins, particularly peptidyl-prolyl isomerase, or rotamase, enzyme activity.
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