Inhibitors of low molecular weight protein tyrosine phosphatase and uses thereof
Inventors
Bottini, Nunzio • Zou, Jiwen • GANJI, Santhi R. • Stanford, Stephanie • Pinkerton, Anthony • Chung, Thomas D. Y. • HEDRICK, MICHAEL • Ardecky, Robert
Assignees
La Jolla Institute for Allergy and Immunology • Sanford Burnham Prebys Medical Discovery Institute
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Publication Number
US-11220486-B2
Publication Date
2022-01-11
Expiration Date
Abstract
Herein are provided, inter alia, compounds capable of modulating the level of activity of low molecular weight protein tyrosine phosphatase (LMPTP) and methods of using the same. In embodiments, the compound has a structure according to Formula (I-A).
Core Innovation
The disclosure relates to low molecular weight protein tyrosine phosphatase (LMPTP) and LMPTP inhibitors, with LMPTP including ACP1 treated as a therapeutic target for obesity and metabolic syndrome, and for related cardiovascular disease indications. It provides small-molecule LMPTP inhibitor compounds, or pharmaceutically acceptable salts thereof, having defined chemical formulas and variable substituent structures.
The core chemical concept is a compound defined by a formula with broad Markush substituent variables, including L1 and R2, as well as phenyl-derived R1 and additional variable groups such as R3 through R6. The substituent framework includes a restriction for R2 with respect to unsubstituted morpholine, and a phenyl substituent group R1A defined as —C(O)NR1C R1D with defined R1C and R1D options, optionally combining with the nitrogen atom to form a substituted or unsubstituted heterocycloalkyl.
The disclosure further characterizes the LMPTP inhibitor concept as an inhibitor of LMPTP activity, and in some embodiments as an allosteric inhibitor. It also includes quinoline/quinazolinone-series analogs, LMPTP inhibitor SAR, pharmaceutical compositions, methods of synthesis, methods of treatment or inhibition for LMPTP activity, and disease-treatment indication lists.
Claims Coverage
The consolidated claim coverage centers on a broad compound class, or pharmaceutically acceptable salt thereof, defined by a core formula with multiple independently selected substituent-variable groups. The inventive features repeated across the inputs are the specific L1 and R2 selections with an explicit exclusion for unsubstituted morpholine, the phenyl-bearing substituent R1A defined as —C(O)NR1C R1D with defined R1C and R1D options, and the additional independently selected substituents R3 through R6 under stated halogen and index constraints. A therapeutic use claim is also present in the provided claims.
Variable-core compound with L1 and R2 heterocycloalkyl excluding morpholine
A compound, or pharmaceutically acceptable salt thereof, having a specified formula where L1 is substituted or unsubstituted C2-C6 alkylene and R2 is substituted or unsubstituted heterocycloalkyl, with the restriction that the heterocycloalkyl is not unsubstituted morpholine.
Phenyl substituent with R1A as —C(O)NR1C R1D
The compound where R1 is phenyl comprising a substituent group R1A, wherein R1A is —C(O)NR1C R1D and R1C and R1D are selected from defined hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl options, including the option that R1C and R1D, together with the nitrogen atom, optionally form a substituted or unsubstituted heterocycloalkyl.
Enumerated substituent variability for R3 through R6
The compound where R3, R4, R5, and R6 are independently selected from hydrogen, halogen, and listed substituted or unsubstituted organic groups, with X independently being F, Cl, Br, or I and with the stated index constraints.
Therapeutic use by administering an effective amount
A method of treating specified diseases or conditions by administering to a subject an effective amount of the compound, or a pharmaceutically acceptable salt, for the listed disease or condition set.
The claims consistently define a Markush compound framework with constrained substituent-variable groups, including the L1/R2 selection, the phenyl-linked R1A group, and broad but defined variability for R3 through R6. The provided claim set also includes a therapeutic administration claim directed to the explicitly listed diseases and conditions.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Biological profiling and SAR of LMPTP inhibitors, including LMPTP/OMFP IC50 profiling and selection of an Entry 50 compound (Compound D1/ML400).
Cell-based efficacy in inhibiting 3T3-L1 adipogenesis by Compound D1.
In vivo and molecular biology evaluation of LMPTP inhibition and insulin-related effects.
ADME/T property evaluation including aqueous solubility, plasma stability, and microsome stability.
Rodent pharmacokinetics evaluation including reported AUC, t1/2, and bioavailability.
Treatment of diabetes, heart disease, coronary artery disease, hyperlipidemia, lipodystrophy, insulin resistance, rheumatic disease, atherosclerosis, myocardial infarction, stroke, high blood pressure (hypertension), obesity, elevated fasting plasma glucose, high serum triglycerides, elevated blood cholesterol, cardiac hypertrophy, heart failure, and metabolic syndrome.
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