Heterocyclic compounds useful in the treatment of disease
Inventors
Beaton, Graham • Tucci, Fabio C. • RAVULA, SATHEESH B. • Shah, Chandravadan R. • LUU, Hiep
Assignees
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Publication Number
US-10570103-B2
Publication Date
2020-02-25
Expiration Date
Abstract
A method for treating a lysophosphatidic acid-dependent disease or condition in a subject in need thereof is provided. The method includes administering to the subject a therapeutically effective amount of a heterocyclic compound. The heterocyclic compound is a lysophosphatidic acid receptor ligand. Lysophosphatidic acid-dependent diseases and conditions include diseases involving fibrosis, such as fibrosis of the heart, kidney, liver and lung, and scleroderma; inflammatory diseases such as diabetic nephropathy and inflammatory bowel disease; ocular diseases such as diseases involving retinal degeneration; nerve diseases such as pruritus and pain.
Core Innovation
The invention provides substituted compounds defined by Formula I, with structural constraints on substituents RA and RB, linkage groups L1 and L2, and ring systems Ring A, Ring B, and Ring C. The disclosed groups include carboxylic acid isostere variants, tetrazolyl, cyano, amide variants, and related substituent and ring variable definitions, together with allowed functional group options and representative structural examples across Formula I, Formula II, and Formula III.
Ring A is specified as a 5 membered heteroarene or a 5- or 6-membered heteroarene depending on the described embodiment, and Rings B and C are defined as cycloalkylene, heterocycloalkylene, arylene, or heteroarylene with optional substitution defined using RH. The disclosure also includes UV-Z motifs, substitution-variable options, and illustrative compound embodiments tied to the scaffold definitions.
Using these Formula I compounds, the patent describes therapeutic use for treating a lysophosphatidic acid-dependent disease or condition in a subject in need thereof. The invention also includes a method for reducing signal transduction through a lysophosphatidic acid receptor (LPAR) by contacting the LPAR with a compound having the structure of Formula I, including a pharmaceutically acceptable salt or prodrug thereof, and pharmaceutical compositions comprising an active compound having the structure of Formula I and a pharmaceutically acceptable excipient.
Claims Coverage
The independent claims cover three related inventive concepts using Formula I compounds: treatment of a lysophosphatidic acid-dependent disease or condition by administration, treatment using a pharmaceutical composition comprising Formula I and a pharmaceutically acceptable excipient, and reducing signal transduction through a lysophosphatidic acid receptor (LPAR) by contacting the receptor. Across these claims, the inventive features are the defined Formula I compound structure and its use in LPA/LPAR-directed therapeutic and composition contexts.
Treatment of a lysophosphatidic acid-dependent disease or condition with a Formula I compound
Administering to a subject in need thereof a therapeutically effective amount of a compound having the structure of Formula I or a pharmaceutically acceptable salt or prodrug thereof, with Formula I defined by substituted ring and linker variables including RA, RB, L1, L2, Ring A, Ring B, and Ring C.
Treatment of a lysophosphatidic acid-dependent disease or condition with a pharmaceutical composition
Administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising an active compound and a pharmaceutically acceptable excipient, the active compound having the structure of Formula I or a pharmaceutically acceptable salt or prodrug thereof.
Reducing lysophosphatidic acid receptor signal transduction by contacting with a Formula I compound
Contacting the LPAR with a compound having the structure of Formula I or a pharmaceutically acceptable salt or prodrug thereof to reduce signal transduction through the receptor.
The claim coverage centers on administering or contacting lysophosphatidic acid receptor targets using heterocyclic Formula I compounds, including pharmaceutically acceptable salt or prodrug forms, and on a pharmaceutical composition embodiment with a pharmaceutically acceptable excipient. The claims are tied to treatment of lysophosphatidic acid-dependent disease or condition and to reducing LPAR signal transduction.
Stated Advantages
Treating a lysophosphatidic acid-dependent disease or condition.
Reducing signal transduction through a lysophosphatidic acid receptor (LPAR).
Documented Applications
Treatment of lysophosphatidic acid-dependent diseases or conditions, including fibrotic organ disease, liver fibrosis, nonalcoholic steatohepatitis (NASH), nephropathy, diabetic nephropathy, glaucoma filtration surgery scarring, cancers, inflammatory diseases, pain, pruritus, ocular diseases, and hepatic, renal, and skin disorders.
Reducing signal transduction through a lysophosphatidic acid receptor (LPAR) by contacting the LPAR with a Formula I compound.
Treatment of a lysophosphatidic acid-dependent disease or condition in a subject in need thereof by administering a therapeutically effective amount of a Formula I compound or a pharmaceutical composition containing a Formula I active compound.
Example 57 includes a receptor binding assay using tritiated lysophosphatidic acid ([3H]-LPA) with CHO cells for LPA1R, with Ki values derived from Scatchard plot analysis.
Example 58 includes a calcium flux assay using FLIPR technology and a Fluo-based No Wash Ca2+ dye in CHO cells for LPA1R, reporting Ca2+ flux IC50 categories, Hill coefficient, EC80, and percentage inhibition/activation.
Table 2 categorizes representative compounds of Formula I-XII by LPA1R Ca2+ flux functional assay Ca2+ flux IC50 categories A/B/C/D.
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