ABSTRACT
The structure-human CXCR3 binding affinity relationship of a series of pyridyl/pyrazinyl-piperazinyl-piperidine derivatives were explored with a focus to improve PK, hERG and metabolic profiles. Several small heterocycles were identified as amide surrogates, which minimized many potential metabolite issues. During the course of SAR development, we have observed the additive effect of desirable functional groups to improve hERG and PK profiles which lead to the discovery of many clinically developable CXCR3 antagonists with excellent overall profile.
Subject(s)
Amides/pharmacology , Drug Discovery , Ether-A-Go-Go Potassium Channels/metabolism , Heterocyclic Compounds/pharmacology , Receptors, CXCR3/antagonists & inhibitors , Amides/administration & dosage , Amides/chemistry , Animals , Dose-Response Relationship, Drug , Heterocyclic Compounds/administration & dosage , Heterocyclic Compounds/chemistry , Humans , Molecular Structure , Rats , Structure-Activity RelationshipABSTRACT
A series of trisubstituted purinones was synthesized and evaluated as A(2A) receptor antagonists. The A(2A) structure-activity relationships at the three substituted positions were studied and selectivity against the A(1) receptor was investigated. One antagonist 12o exhibits a K(i) of 9nM in an A(2A) binding assay, a K(b) of 18nM in an A(2A) cAMP functional assay, and is 220-fold selective over the A(1) receptor.
Subject(s)
Adenosine A2 Receptor Antagonists , Purinones/chemical synthesis , Animals , Humans , Protein Binding/drug effects , Protein Binding/physiology , Purinones/metabolism , Purinones/pharmacology , Rats , Receptor, Adenosine A2A/metabolism , Recombinant Proteins/antagonists & inhibitors , Recombinant Proteins/metabolism , Structure-Activity RelationshipABSTRACT
Among the proteinogenic amino acids, only proline is a secondary amine and only proline has a saturated ring. Electronegative substituents on C-4 (that is, C(gamma)) have a substantial effect on the trans/cis ratio of the prolyl peptide bond and the pucker of the pyrrolidine ring. 2-Azabicyclo[2.1.1]hexane is, in essence, a proline analogue with two C(gamma) atoms, one in each of the two prevalent ring puckers of proline. Here, 2-azabicyclo[2.1.1]hexane analogues of 2S-proline, (2S,4S)-4-hydroxyproline, and (2S,4S)-4-fluoroproline residues were synthesized, and their trans/cis ratios were shown to be invariant in a particular solvent. Thus, the substitution of a proline residue on C-4 affects the trans/cis ratio by altering the pucker of its pyrrolidine ring. This finding has implications for the conformation of collagen, which has an abundance of 2S-proline and (2S,4R)-4-hydroxyproline residues, and can be stabilized by (2S,4R)-4-fluoroproline and (2S,4S)-4-fluoroproline residues.
