Heterocyclic autotaxin inhibitors and uses thereof
Inventors
ROPPE, Jeffrey Roger • Parr, Timothy Andrew • Hutchinson, John Howard
Assignees
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Publication Number
US-9260416-B2
Publication Date
2016-02-16
Expiration Date
Abstract
Described herein are compounds that are inhibitors of autotaxin. Also described are pharmaceutical compositions and medicaments that include the compounds described herein, as well as methods of using such inhibitors, alone and in combination with other compounds, for treating autotaxin-dependent or autotaxin-mediated conditions or diseases.
Core Innovation
The patent discloses autotaxin (ATX) inhibitors in the form of compounds of Formula (I), or pharmaceutically acceptable salts thereof, solvates, and prodrugs. The compounds are defined by a heteroaryl core where ring A is a heteroaryl and X is —S—, with multiple substituent positions specified by R1, R2, RA, R3, R5, R6, R9, R10, L2, and n.
The disclosed structural framework constrains R1, ring A, R2, RA, L2, R3, R5, and R6 within defined substitution limits, and includes scaffold variants expressed as Formula (II) and Formula (III). The patent also states that the compounds inhibit ATX activity, thereby reducing lysophosphatidic acid (LPA) signaling in the ATX-LPA signaling axis.
The document further describes pharmaceutical compositions containing the claimed ATX inhibitory compounds. Example compounds include sulfanyl-linked indole/pyridine-pyrazole-carboxylic acid derivatives and related nicotinic, isonicotinic, pyridine-2-carboxylic acid, and pyrazolyl-acetic acid structures.
Claims Coverage
The consolidated claim coverage centers on Formula (I) compounds with a sulfur linkage (X = —S—) and constrained substituent patterns across R1, ring A, R2, RA, L2, R3, R5, R6, and n. Across the provided claim content, five inventive features are identifiable, including the compound scaffold, narrower ring and substituent selections, specific enumerated derivative groups, and a pharmaceutical composition.
Formula (i) autotaxin inhibitor scaffold
A compound of Formula (I), or a pharmaceutically acceptable salt thereof, having a substituted or unsubstituted monocyclic heteroaryl as R1, ring A as a heteroaryl, R2 selected from H, C1-C4 alkyl or C1-C4 fluoroalkyl, X as —S—, L2 being absent, C1-C6 alkylene, or C3-C6 cycloalkylene, RA selected from carboxylic acid, ester, hydroxyl, cyano, boronic acid, acylamino and related groups, R3 and R5 each independently selected from the listed halogen/hydroxyl/cyano/alkyl/alkoxy/thioalkyl/fluoroalkyl/fluoroalkoxy/heteroalkyl options, and R6 selected from the listed functional options including halogen and multiple carbonyl/heteroatom-containing substituent classes; where n is 0, 1, or 2.
Monocyclic 6-membered ring A and fixed ra and l2 options
A compound having ring A as a monocyclic 6-membered heteroaryl, L2 being absent or —CH2—, RA being —CO2H, and R6 being one of the specified substituents including halogens, —CN, —OH, alkyl/alkoxy options, and —S—CH3.
Pyrazolyl r1 and restricted r3/r5 substituent sets
A compound, or a pharmaceutically acceptable salt, defining R1 as a substituted or unsubstituted pyrazolyl with each substituent being within the C1-C4 alkyl class, with ring A selected from specific heteroaryl types including pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl, X being —S—, and R3 and R5 being restricted to defined substituent options including H, F, Cl, and —CN and alkyl/alkoxy sets limited to the C1-C4 class.
Specific substituted sulfanyl-linked nicotinic and pyrazolyl-acetic acid derivatives
A compound selected among specified substituted nicotinic acid, isonicotinic acid, pyridine-2-carboxylic acid, or acetic-acid derivative structures featuring chloro and optional fluoro substitution together with methyl/ethyl/isopropyl/propyl-substituted pyrazolyl groups connected via a sulfanyl linkage to indole or pyridine scaffolds.
Pharmaceutical composition with a claimed compound
A pharmaceutical composition containing a compound of claim 1, or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable excipient.
The claim coverage is organized around sulfur-linked heteroaryl compounds of Formula (I) with constrained substitution patterns, with dependent claims further narrowing ring A, L2, and substituent sets at R3, R5, and R6. Additional coverage includes enumerated substituted nicotinic, isonicotinic, pyridine-2-carboxylic, and pyrazolyl-acetic acid derivatives, plus a pharmaceutical composition containing the claimed compound and pharmaceutically acceptable excipients.
Stated Advantages
Reduces lysophosphatidic acid (LPA) signaling by inhibiting autotaxin (ATX) activity.
Substantial in vitro/in vivo autotaxin inhibition for native and human-serum autotaxin.
IC50-based categorization using bands A (<0.3 μM), B (0.3–1.0 μM), and C (>1.0 μM) for inhibition characterization.
Documented Applications
Treatment or therapeutic use of conditions associated with ATX/LPA modulation across fibrosis, including idiopathic pulmonary fibrosis and lung, renal, hepatic, and cutaneous fibrosis.
Treatment or therapeutic use of conditions associated with ATX/LPA modulation in cancer and metastasis, including multiple cancers.
Treatment or therapeutic use of conditions associated with ATX/LPA modulation in inflammatory/autoimmune disorders, including rheumatoid arthritis, psoriasis, and related inflammatory/autoimmune conditions.
Treatment or therapeutic use of pain associated with ATX/LPA modulation, including neuropathic pain.
Treatment or therapeutic use of cardiovascular and angiogenesis-related conditions, including atherosclerosis and hypertension.
Treatment or therapeutic use of asthma/COPD.
Treatment or therapeutic use of ocular fibrosis, including AMD.
Native and human-serum autotaxin inhibition using conditioned medium or delipidated/Opticlear human serum with LPC substrate.
Choline oxidase/peroxidase colorimetric detection at 555 nm to characterize autotaxin inhibition by IC50-based banding (A/B/C).
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