FAP inhibitors
Inventors
Jansen, Koen • De Meester, Ingrid • Heirbaut, Leen • Cheng, Jonathan D • Joossens, Jurgen • Augustyns, Koen • Van Der Veken, Pieter
Assignees
Universiteit Antwerpen • Fox Chase Cancer Center • Institute for Cancer Research
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Publication Number
US-9346814-B2
Publication Date
2016-05-24
Expiration Date
Abstract
The present invention relates to novel inhibitors having high selectivity and specificity for FAP (fibroblast activation protein). Said inhibitors are useful as a human and/or veterinary medicine, in particular for the treatment and/or prevention of FAP-related disorders such as but not limited to proliferative disorders.
Core Innovation
The invention relates to compounds of Formula X, including stereoisomers, tautomers, racemic mixtures, salts, hydrates, and solvates, defined by substituent-variable constraints for R1 through R14 and a 5 to 10-membered N-containing aromatic or non-aromatic mono- or bicyclic heterocycle framework. The structural definition further specifies aromatic monocycle groups Ar1, Ar2, and Ar3 and non-aromatic monocycle group Het2, each optionally substituted according to the allowed substituent classes.
The disclosed embodiments include quinoline/heteroaryl scaffold examples bearing a cyanopyrrolidine-1-yl group, including quinoline-4-carboxamide and quinoline-4-carboxylic acid related structures with a cyanopyrrolidine-1-yl-containing substituent such as 2-(2-cyanopyrrolidine-1-yl)-2-oxoethyl. The invention seeks novel, selective and stable FAP inhibitors with improved SAR versus known dipeptidyl boronic-acid inhibitors, and uses a carbonitrile warhead rationale for selectivity against related S9b proteases, including DPP4/DPP8/9/DPP2 and PREP.
The invention is associated with biochemical evaluation against fibroblast activation protein (FAP), with enzymatic IC50 values reported for FAP versus related enzymes including DPPIV, DPP9, DPP2, and PREP. Selectivity and positional SAR commentary is provided, including that the 4-quinolinoyl positional isomer shows best FAP affinity and that other positional isomers show very low affinity.
Claims Coverage
The consolidated claim coverage centers on Formula X compounds with detailed substituent-variable constraints and an N-containing mono- or bicyclic heterocycle framework. The claim coverage also includes a pharmaceutical composition containing the compound and a method to inhibit fibroblast activation protein (FAP) activity by administering an effective amount of the compound to a subject.
Formula X compound with N-containing heterocycle framework
A compound of Formula X or a stereoisomer, tautomer, racemic, salt, hydrate, or solvate thereof, wherein R1 and R2 are each independently selected from H, OH, halo, C1-6 alkyl, O-C1-6 alkyl, and S-C1-6 alkyl; R3 is selected from H, CN, B(OH)2, C(O)alkyl, C(O)aryl, C-C(O)aryl, C-C-S(O)2 aryl, CO2H, SO3H, SO2NH2, PO3H2, and 5-tetrazolyl; R4 is H; and R5, R6, and R7 are each independently selected from H, OH, oxo, halo, C1-6 alkyl, O-C1-6 alkyl, S-C1-6 alkyl, NR8R9, OR12-Het2, and Ar2, with further definitions for Ar1, Ar2, Ar3, Het2, and n.
Pharmaceutical composition containing the compound of Formula X
A pharmaceutical composition that includes the compound of claim 1, formulated for use as a human or veterinary medicine.
Method of inhibiting fibroblast activation protein activity
A method to inhibit fibroblast activation protein (FAP) activity by administering an effective amount of the compound of claim 1 to a subject who needs it.
The claim coverage establishes a compound genus defined by Formula X with extensive substituent and heterocycle constraints, and extends to a pharmaceutical composition and a FAP inhibition method.
Stated Advantages
High selectivity, supported by markedly reduced potency toward off-target proteases.
Improved SAR versus known dipeptidyl boronic-acid inhibitors.
Plasma stability, supported by early SAR reporting.
Low nanomolar FAP inhibition, supported by representative affinity/selectivity results.
FAP potency: FAP IC50 <10 µM, often <1 µM.
Higher selectivity for FAP versus DPPIV/DPP8/DPP9/DPP2 and PREP.
Inhibition of both endo- and exopeptidase activities of FAP.
Plasma functional stability with minimal IC50 shift after >12 h in rat/human plasma.
Limited plasma shifts for endogenous FAP activity in plasma.
Biochemical selectivity and affinity are reported relative to related DPP family enzymes and PREP, including that the 4-quinolinoyl positional isomer shows best FAP affinity.
Reduced activity toward off-target proteases is reported through comparison to DPPIV, DPP9, DPP2, and PREP.
Documented Applications
Prevention or treatment of FAP-related disorders using a human medicament or veterinary medicament, including proliferative diseases such as breast, colorectal, ovarian, prostate, pancreatic, kidney, lung, and melanoma.
Prevention or treatment of tissue remodeling/chronic inflammation conditions such as fibrosis, wound healing, keloid, osteoarthritis, rheumatoid arthritis, atherosclerosis, and Crohn’s disease.
Use in endocrinological dysfunction/glucose metabolism contexts.
Use in blood clotting disorders contexts.
Biological evaluation of invention compounds for inhibition of fibroblast activation protein (FAP) activity, including endo- and exopeptidase activities, with selectivity comparisons versus DPPIV/DPP8/DPP9/DPP2 and PREP.
Preclinical plasma functional stability assessment in rat plasma and human plasma, including evaluation of IC50 shift and effects on endogenous FAP activity in plasma.
Inhibition of fibroblast activation protein (FAP) activity by administering an effective amount of the compound to a subject in need thereof.
Use in a pharmaceutical composition for human medicine or veterinary medicine that includes the compound of claim 1.
Use of a pharmaceutical composition including pharmaceutically acceptable carriers, diluents, excipients, or adjuvants.
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