Synthesis, structure-property relationships and pharmacokinetic evaluation of ethyl 6-aminonicotinate sulfonylureas as antagonists of the P2Y₁₂ receptor. 2013

Peter Bach, and Jonas Boström, and Kay Brickmann, and J J J van Giezen, and Robert D Groneberg, and Darren M Harvey, and Michael O'Sullivan, and Fredrik Zetterberg
Department of Medicinal Chemistry, AstraZeneca R&D Mölndal, Pepparedsleden 1, S-43183 Mölndal, Sweden. bach@chalmers.se

The present paper describes the development of a new series of P2Y12 receptor antagonists based on our previously reported piperazinyl urea series 1 (IC50 binding affinity = 0.33 μM, aq solubility <0.1 μM, microsomal CLint (HLM) ≥300 μM/min/mg). By replacement of the urea functionality with a sulfonylurea group we observed increased affinity along with improved stability and solubility as exemplified by 47 (IC50 binding affinity = 0.042 μM, aq solubility = 90 μM, microsomal CLint (HLM) = 70 μM/min/mg). Further improvements in affinity and metabolic stability were achieved by replacing the central piperazine ring with a 3-aminoazetidine as exemplified by 3 (IC50 binding affinity = 0.0062 μM, aq solubility = 83 μM, microsomal CLint (HLM) = 28 μM/min/mg). The improved affinity observed in the in vitro binding assay also translated to the potency observed in the WPA aggregation assay (47: 19 nM and 3: 9.5 nM) and the observed in vitro ADME properties translates to the in vivo PK properties observed in rat. In addition, we found that the chemical stability of the sulfonylureas during prolonged storage in solution was related to the sulfonyl urea linker and depended on the type of solvent and the substitution pattern of the sulfonyl urea functionality.

UI MeSH Term Description Entries
D009539 Nicotinic Acids 2-, 3-, or 4-Pyridinecarboxylic acids. Pyridine derivatives substituted with a carboxy group at the 2-, 3-, or 4-position. The 3-carboxy derivative (NIACIN) is active as a vitamin. Acids, Nicotinic
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D013329 Structure-Activity Relationship The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups. Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships
D014508 Urea A compound formed in the liver from ammonia produced by the deamination of amino acids. It is the principal end product of protein catabolism and constitutes about one half of the total urinary solids. Basodexan,Carbamide,Carmol
D015394 Molecular Structure The location of the atoms, groups or ions relative to one another in a molecule, as well as the number, type and location of covalent bonds. Structure, Molecular,Molecular Structures,Structures, Molecular
D051381 Rats The common name for the genus Rattus. Rattus,Rats, Laboratory,Rats, Norway,Rattus norvegicus,Laboratory Rat,Laboratory Rats,Norway Rat,Norway Rats,Rat,Rat, Laboratory,Rat, Norway,norvegicus, Rattus
D058921 Purinergic P2Y Receptor Antagonists Compounds that bind to and block the stimulation of PURINERGIC P2Y RECEPTORS. Included under this heading are antagonists for specific P2Y receptor subtypes. ADP Receptor Antagonist,ADP Receptor Blocker,Adenosine Diphosphate Receptor Antagonist,P2Y Purinoceptor Antagonist,P2Y1 Purinoceptor Antagonist,P2Y12 Purinoceptor Antagonist,P2Y12 Receptor Antagonist,P2Y2 Purinoceptor Antagonist,Purinergic P2Y Receptor Antagonist,Purinergic P2Y1 Receptor Antagonist,Purinergic P2Y12 Receptor Antagonist,Purinergic P2Y2 Receptor Antagonist,ADP Receptor Antagonists,ADP Receptor Blockers,Adenosine Diphosphate Receptor Antagonists,P2Y Purinoceptor Antagonists,P2Y1 Purinoceptor Antagonists,P2Y12 Purinoceptor Antagonists,P2Y12 Receptor Antagonists,P2Y2 Purinoceptor Antagonists,Purinergic P2Y1 Receptor Antagonists,Purinergic P2Y12 Receptor Antagonists,Purinergic P2Y2 Receptor Antagonists,Antagonist, ADP Receptor,Antagonist, P2Y Purinoceptor,Antagonist, P2Y1 Purinoceptor,Antagonist, P2Y12 Purinoceptor,Antagonist, P2Y12 Receptor,Antagonist, P2Y2 Purinoceptor,Antagonists, ADP Receptor,Antagonists, P2Y Purinoceptor,Antagonists, P2Y1 Purinoceptor,Antagonists, P2Y12 Purinoceptor,Antagonists, P2Y12 Receptor,Antagonists, P2Y2 Purinoceptor,Blocker, ADP Receptor,Purinoceptor Antagonist, P2Y,Purinoceptor Antagonist, P2Y1,Purinoceptor Antagonist, P2Y12,Purinoceptor Antagonist, P2Y2,Purinoceptor Antagonists, P2Y,Purinoceptor Antagonists, P2Y1,Purinoceptor Antagonists, P2Y12,Purinoceptor Antagonists, P2Y2,Receptor Antagonist, ADP,Receptor Antagonist, P2Y12,Receptor Antagonists, ADP,Receptor Antagonists, P2Y12,Receptor Blocker, ADP,Receptor Blockers, ADP
D058925 Receptors, Purinergic P2Y12 A subclass of purinergic P2Y receptors that have a preference for ADP binding and are coupled to GTP-BINDING PROTEIN ALPHA SUBUNIT, GI. The P2Y12 purinergic receptors are found in PLATELETS where they play an important role regulating PLATELET ACTIVATION. P2T Purinoceptor,P2Y(ADP) Receptor,P2Y(T) Receptor,P2Y12 Purinoceptor,P2Y12 Purinoceptors,Purinergic Receptor P2Y, G-Protein Coupled, 12,Purinergic Receptor P2Y12,Purinoceptor P2T,Purinoceptor P2Y12,P2T, Purinoceptor,P2Y12 Receptors, Purinergic,P2Y12, Purinergic Receptor,P2Y12, Purinoceptor,Purinergic P2Y12 Receptors,Purinoceptor, P2T,Purinoceptor, P2Y12,Purinoceptors, P2Y12

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