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1.
ACS Med Chem Lett ; 13(7): 1165-1171, 2022 Jul 14.
Article in English | MEDLINE | ID: mdl-35859878

ABSTRACT

We describe the synthesis of triazole-containing carboline derivatives and their utility as bromodomain and extra-terminal (BET) inhibitors. A convergent synthetic route permitted the detailed investigation of deuteration and fluorination strategies to reduce clearance while maintaining a favorable in vitro profile. This work led to the identification of a potent BET inhibitor, 2-{8-fluoro-3-[4-(2H3)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-(oxan-4-yl)(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol (15), which demonstrated reduced clearance and an improved pharmacokinetic (PK) profile across preclinical species. Importantly, no major metabolite was observed when 15 was incubated with human hepatocytes (hHEP) for 2 h. This study culminated with the evaluation of 15 in a mouse triple-negative breast cancer (TNBC) tumor model where it demonstrated robust efficacy at low doses.

2.
Bioorg Med Chem Lett ; 26(2): 662-666, 2016 Jan 15.
Article in English | MEDLINE | ID: mdl-26631321

ABSTRACT

A novel cyclohexenyl series of CCR2 antagonists has been discovered. This series of small, rigid compounds exhibits submicromolar binding affinity for CCR2. Modification of the substituents on the cyclohexene ring led to the identification of potent CCR2 antagonists. Progress from initial lead 5 (IC50=700nM) to (-)-38 (IC50=9.0nM) is discussed.


Subject(s)
Cyclohexenes/chemistry , Cyclohexenes/pharmacology , Receptors, CCR2/antagonists & inhibitors , Cyclohexenes/chemical synthesis , Drug Discovery , Humans , Models, Molecular , Receptors, CCR2/metabolism , Structure-Activity Relationship
3.
Bioorg Med Chem Lett ; 18(2): 576-85, 2008 Jan 15.
Article in English | MEDLINE | ID: mdl-18096386

ABSTRACT

Conformational analysis of trans-1,2-disubstituted cyclohexane CCR3 antagonist 2 revealed that the cyclohexane linker could be replaced by an acyclic syn-alpha-methyl-beta-hydroxypropyl linker. Synthesis and biological evaluation of mono- and disubstituted propyl linkers support this conformational correlation. It was also found that the alpha-methyl group to the urea lowered protein binding and that the beta-hydroxyl group lowered affinity for CYP2D6. Ab initio calculations show that the alpha-methyl group governs the spatial orientation of three key functionalities within the molecule. alpha-Methyl-beta-hydroxypropyl urea 31 with a chemotaxis IC(50)=38 pM for eosinophils was chosen to enter clinical development for the treatment of asthma.


Subject(s)
Chemotaxis, Leukocyte/drug effects , Eosinophils/drug effects , Piperidines/pharmacology , Receptors, CCR3/antagonists & inhibitors , Urea/analogs & derivatives , Administration, Oral , Animals , Cytochrome P-450 Enzyme Inhibitors , Dogs , Eosinophils/cytology , Hydrogen Bonding , Mice , Molecular Conformation , Piperidines/chemistry , Piperidines/pharmacokinetics , Rats , Structure-Activity Relationship , Urea/chemistry , Urea/pharmacokinetics , Urea/pharmacology
4.
Bioorg Med Chem Lett ; 12(13): 1785-9, 2002 Jul 08.
Article in English | MEDLINE | ID: mdl-12067561

ABSTRACT

CCR3 antagonist leads with IC(50) values in the microM range were converted into low nM binding compounds that displayed in vitro inhibition of human eosinophil chemotaxis induced by human eotaxin. In particular, 4-benzylpiperidin-1-yl-n-propylureas and erythro-3-(4-benzyl-2-(alpha-hydroxyalkyl)piperidin-1-yl)-n-propylureas (obtained via Beak reaction of N-BOC-4-benzylpiperidine) exhibited single digit nanomolar IC(50) values for CCR3.


Subject(s)
Anti-Asthmatic Agents/chemistry , Anti-Asthmatic Agents/pharmacology , Receptors, Chemokine/antagonists & inhibitors , Alkylation , Amides/chemistry , Amides/metabolism , Calcium/metabolism , Chemokine CCL11 , Chemokines, CC/metabolism , Chemotaxis, Leukocyte/drug effects , Humans , Inhibitory Concentration 50 , Ligands , Piperidines/chemistry , Receptors, CCR3 , Receptors, Chemokine/chemistry , Receptors, Chemokine/metabolism , Stereoisomerism , Structure-Activity Relationship
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