Creatine prodrugs, compositions and methods of use thereof
Inventors
CHAN, Yiumo • Kakkis, Emil D. • Trotier-Faurion, Alexandra • Brubaker, William F. • NATESAN, ARJUN • Lee, Paul • FYFFE-MARICICH, SHARYL • Lapointe, David • Lizarzaburu, Mike E.
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-11332438-B2
Publication Date
2022-05-17
Expiration Date
Abstract
The present disclosure provides creatine prodrug analogs and their compositions useful for the treatment of creatine deficiencies.
Core Innovation
The invention relates to compounds of Formula (I), Formula (II), Formula (I-A), and Formula (III)/(III-A), and pharmaceutically acceptable salts and solvates. The core structure is characterized by substituent groups R, R2, R3, R4, R5, and a ring-forming relationship between R6 and R1, with R selected from CH3, CH2D, CHD2, or CD3. The disclosure also includes deuterated creatine prodrugs, deuterated creatine analogs, and deuterated 1-oxa-4,6-diazacycloalkane-2,7-dione derivatives, together with specific salt forms such as sodium salt, hydrochloride salt, and hydrochloric acid salt forms.
A key structural element is that R6 and R1 together form an alkylene group or an alkenylene group that, together with the atoms each is bonded to, forms a 12 to 25 membered ring. In forming this alkylene or alkenylene segment, 1, 2, 3, or 4 CH2 units are optionally replaced with a heteroatom selected from O, S, or N, provided that no adjacent CH2 is replaced, and the alkylene or alkenylene group is optionally substituted with one or more R4. Two R4 groups on the same or adjacent carbon can form a 3 to 6 membered fused or spiro cycloalkyl ring or a 3 to 6 membered fused or spiro heterocyclic ring.
The compounds are described as shielding negative charge and increasing hydrophobicity to support blood-brain barrier, neuron, and glial uptake, while avoiding or minimizing creatine dehydration to creatinine via non-enzymatic cyclization. The prodrugs are described as cleavable in the brain via fatty acid amide hydrolase (FAAH1/2), and the document further describes pharmaceutical compositions, sustained release dosage forms, and deuterated creatine such as d3-creatine for improved detection versus endogenous creatine.
Claims Coverage
The consolidated claim coverage centers on Formula (I) compound claims and additional structure-defined compound claims. Across the cited claim sets, the inventive features consistently include deuterated isotopic substitution, a 12 to 25 membered alkylene or alkenylene ring architecture with optional heteroatom replacement, optional fused or spiro ring formation from paired R4 groups, and pharmaceutically acceptable salt or solvate options. Some claim sets also include pharmaceutical compositions and methods of treating specified diseases.
Formula (I) compound with defined deuterated R and substituent pattern
A compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is CH3, CH2D, CHD2, or CD3; R2 is hydrogen, C(O)NHR5, C(O)OR5, C(O)(linear or branched alkyl), or C(O)(linear or branched alkenyl); R3 is C(O)OR6; and R4 is halogen, OH, OR5, oxo, NH2, NHR5, N(R5)2, NO2, CF3, C1-C6 alkyl, or C1-C6 haloalkyl.
12 to 25 membered alkylene or alkenylene ring formation from R6 and R1 with optional heteroatom replacement
R6 and R1 together form an alkylene group or an alkenylene group which, with the atoms to which they are each bonded, forms a 12 to 25 membered ring, wherein 1, 2, 3, or 4 CH2 units are optionally replaced with O, S, or N, provided that no adjacent CH2 is replaced, and wherein the alkylene or alkenylene group is optionally substituted with one or more R4.
Optional fused or spiro ring formation from two R4 groups
Two R4 groups on the same or adjacent carbon can form a 3 to 6 membered fused or spiro cycloalkyl ring or a 3 to 6 membered fused or spiro heterocyclic ring.
Structure-defined compound with pharmaceutically acceptable salt
A compound having the structure shown in the figures, or a pharmaceutically acceptable salt thereof.
Pharmaceutical composition with pharmaceutically acceptable carrier
A pharmaceutical composition includes a compound of Formula (I), or a pharmaceutically acceptable salt or solvate of that compound, together with a pharmaceutically acceptable carrier.
Method of treating a disease by administering a therapeutically effective amount
A method for treating a specified disease by administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof.
Overall, the claim coverage is centered on Formula (I) compound families defined by deuterated and substituent-specific options, a 12 to 25 membered alkylene or alkenylene ring with optional heteroatom replacement and optional fused or spiro 3 to 6 membered rings, together with structure-defined compound claims and dependent coverage for pharmaceutical compositions and disease-treatment administration.
Stated Advantages
Modulates creatine metabolism through negative charge shielding and increased hydrophobicity to support blood-brain barrier, neuron, and glial uptake.
Provides brain cleavage via fatty acid amide hydrolase (FAAH1/2) to support creatine availability in the brain.
Improves detection of deuterated creatine versus endogenous creatine.
Minimizes creatine dehydration to creatinine via non-enzymatic cyclization.
Allows creatine release into cytoplasm while contrasting undesired cyclization to creatinine.
Membrane permeability and creatine delivery independent of the creatine transporter.
Longer fatty acid amides (C11-C18) and unmodified free COOH favor net d3-creatine release and minimize cyclization.
The disclosure associates certain prodrug embodiments with cleavage outcomes in rFAAH and mouse/human brain homogenates and reports stability metrics across microsomes, simulated intestinal fluid, simulated gastric fluid, and plasma.
Documented Applications
Targeting energy metabolism dysfunctions including creatine transporter deficiency (CTD) and cerebral creatine deficiency syndrome (CCDS).
Therapeutic use in ischemia and ischemic reperfusion injury.
Therapeutic use in oxidative stress.
Therapeutic use in neurodegenerative disease or neurodegenerative disorders.
Therapeutic use in cardiovascular disease and heart failure.
Therapeutic use for genetic diseases affecting the creatine kinase system, including creatine transporter or synthesis disorders, multiple sclerosis, and psychotic disorder.
Therapeutic use for muscle fatigue.
Schizophrenia, including positive, negative, and cognitive symptoms.
Bipolar disorder.
Anxiety.
Depressive disorders as supported by referenced depression rating scales.
Cell culture uptake and release studies using ARPE-19 cells and studies in Phenocell iPSC-derived neurons.
Downstream in vivo or translation context involving brain delivery and outcomes comparing d3-creatine versus d3-creatinine, including macrocycle versus linear prodrugs.
In vitro stability and release or cyclization evaluation of deuterated creatine prodrugs, including microsome stability, simulated intestinal fluid, simulated gastric fluid, plasma stability, and in vitro cleavage outcomes measured using rFAAH and mouse or human brain homogenates with percent d3-creatine release and percent d3-creatinine formation.
Interested in licensing this patent?