Abstract
Summary: The invention in this patent application relates to 1-butanoylpiperidine derivatives represented generally by formula (I). These compounds inhibit the activity of tankyrases (TNKS) and poly(ADP-ribose)polymerase-1 (PARP-1) and may provide useful treatment for diseases such as cancer, multiple sclerosis, cardiovascular diseases, central nervous system injury, and different forms of inflammation. The poly(ADP-ribose) polymerase (PARP) protein superfamily performs several cellular processes such as DNA repair, Wnt-signaling, mitoticapparatusformation,andcelldeath.Membersofthefamilymediatethepost-translationalpoly(ADP-ribosyl)ationmodificationof targetedproteinsemployingthecatalyticfunctionofnicotinamideadeninedinucleotide(NAD).Theyalsomediatethepolymerizationof ADP-riboses via glycosidic bonds, creating long and branched ADP-ribose polymers. These polymers are thought to modify protein functions.Someof themembersofthisgrowingfamilyofenzymesarenamedpoly(ADP-ribose) polymerases(PARPs) such asPARP-1, PARP-2, PARP-3, and Vault-PARP. Other members of the family are named tankyrases (TNKS), such as TNKS-1 and TNKS-2. In humans, the PARP family members are encoded by 17 different genes. The first identified and the most studied member of the family is the nuclear enzyme PARP-1. For some time, it remained as the only known enzyme with poly(ADP-ribosyl)ation activity until studies showed that PARP-1 knock out mice can still perform poly(ADP-ribosyl)ation functions, suggesting the existence of other similar enzymes. Following these studies, researchers identified several other family members, although most of them are less studied. PARP-1 contains three major functional domains: an amino terminal DNA-binding domain (DBD), a central automodification domain (AMD),andacarboxyterminalcatalyticdomain(CD).StudieshaveshownthatPARP-1isoverexpressedinavarietyofcancersandhas been linked to prognosis of cancers, most notably breast cancer. A variety of endogenous and exogenous stress signals including those generated by oxidative, genotoxic, thermal, oncogenic, metabolic, and inflammatory stresses can trigger responses from PARP-1 that may in turn trigger pathological conditions such as cancer, inflammation related diseases, autoimmune diseases, neurodegenerative diseases,andmetabolicstresses.Thus,theinhibitionofPARP-1activitiesmaybebeneficialasatherapeutictargettotreatthesediseases. Tankyrasescontainankyrin-repeatproteininteractiondomain,asterile α-motifoligomerizationdomain(SAM),andaPARPcatalyticdomain (PCD),whichdifferentiates themfromothermembersof the PARPfamily.TNKS-1andTNKS-2(a.k.a.PARP-5AandPARP-5B) perform several cellular functions, including telomere homeostasis, mitotic spindle formation, vesicle transport linked to glucose metabolism, Wnt-β-catenin signaling, and viral replication. TNKS-1 activity appears to be essential for the polymerization of mitotic spindle-associated poly(ADP-ribose) andtheaccurateformationandmaintenanceofspindlebipolarity.Furthermore,itsactivityisrequiredfornormaltelomere
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