title: Discovery of a Potent and Orally Bioavailable Dual Antagonist of CC Chemokine Receptors 2 and 5.
abstract: We describe the hybridization of our previously reported acyclic and cyclic CC chemokine receptor 2 (CCR2) antagonists to lead to a new series of dual antagonists of CCR2 and CCR5. Installation of a γ-lactam as the spacer group and a quinazoline as a benzamide mimetic improved oral bioavailability markedly. These efforts led to the identification of 13d, a potent and orally bioavailable dual antagonist suitable for use in both murine and monkey models of inflammation.
authors.affiliation: Departments of Discovery Chemistry, Lead Discovery & Optimization, Preclinical Candidate Optimization, Molecular Discovery Technologies, and Disease Sciences & Biology, Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543, United States.
authors.forename: Percy H
authors.initials: PH
authors.lastname: Carter
authors.affiliation: Departments of Discovery Chemistry, Lead Discovery & Optimization, Preclinical Candidate Optimization, Molecular Discovery Technologies, and Disease Sciences & Biology, Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543, United States.
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Brown
authors.affiliation: Departments of Discovery Chemistry, Lead Discovery & Optimization, Preclinical Candidate Optimization, Molecular Discovery Technologies, and Disease Sciences & Biology, Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543, United States.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Cherney
authors.affiliation: Departments of Discovery Chemistry, Lead Discovery & Optimization, Preclinical Candidate Optimization, Molecular Discovery Technologies, and Disease Sciences & Biology, Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543, United States.
authors.forename: Douglas G
authors.initials: DG
authors.lastname: Batt
authors.affiliation: Departments of Discovery Chemistry, Lead Discovery & Optimization, Preclinical Candidate Optimization, Molecular Discovery Technologies, and Disease Sciences & Biology, Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543, United States.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.affiliation: Departments of Discovery Chemistry, Lead Discovery & Optimization, Preclinical Candidate Optimization, Molecular Discovery Technologies, and Disease Sciences & Biology, Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543, United States.
authors.forename: Cheryl M
authors.initials: CM
authors.lastname: Clark
authors.affiliation: Departments of Discovery Chemistry, Lead Discovery & Optimization, Preclinical Candidate Optimization, Molecular Discovery Technologies, and Disease Sciences & Biology, Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543, United States.
authors.forename: Mary Ellen
authors.initials: ME
authors.lastname: Cvijic
authors.affiliation: Departments of Discovery Chemistry, Lead Discovery & Optimization, Preclinical Candidate Optimization, Molecular Discovery Technologies, and Disease Sciences & Biology, Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543, United States.
authors.forename: John V
authors.initials: JV
authors.lastname: Duncia
authors.affiliation: Departments of Discovery Chemistry, Lead Discovery & Optimization, Preclinical Candidate Optimization, Molecular Discovery Technologies, and Disease Sciences & Biology, Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543, United States.
authors.forename: Soo S
authors.initials: SS
authors.lastname: Ko
authors.affiliation: Departments of Discovery Chemistry, Lead Discovery & Optimization, Preclinical Candidate Optimization, Molecular Discovery Technologies, and Disease Sciences & Biology, Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543, United States.
authors.forename: Sandhya
authors.initials: S
authors.lastname: Mandlekar
authors.affiliation: Departments of Discovery Chemistry, Lead Discovery & Optimization, Preclinical Candidate Optimization, Molecular Discovery Technologies, and Disease Sciences & Biology, Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543, United States.
authors.forename: Ruowei
authors.initials: R
authors.lastname: Mo
authors.affiliation: Departments of Discovery Chemistry, Lead Discovery & Optimization, Preclinical Candidate Optimization, Molecular Discovery Technologies, and Disease Sciences & Biology, Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543, United States.
authors.forename: David J
authors.initials: DJ
authors.lastname: Nelson
authors.affiliation: Departments of Discovery Chemistry, Lead Discovery & Optimization, Preclinical Candidate Optimization, Molecular Discovery Technologies, and Disease Sciences & Biology, Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543, United States.
authors.forename: Jian
authors.initials: J
authors.lastname: Pang
authors.affiliation: Departments of Discovery Chemistry, Lead Discovery & Optimization, Preclinical Candidate Optimization, Molecular Discovery Technologies, and Disease Sciences & Biology, Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543, United States.
authors.forename: Anne V
authors.initials: AV
authors.lastname: Rose
authors.affiliation: Departments of Discovery Chemistry, Lead Discovery & Optimization, Preclinical Candidate Optimization, Molecular Discovery Technologies, and Disease Sciences & Biology, Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543, United States.
authors.forename: Joseph B
authors.initials: JB
authors.lastname: Santella
authors.affiliation: Departments of Discovery Chemistry, Lead Discovery & Optimization, Preclinical Candidate Optimization, Molecular Discovery Technologies, and Disease Sciences & Biology, Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543, United States.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Tebben
authors.affiliation: Departments of Discovery Chemistry, Lead Discovery & Optimization, Preclinical Candidate Optimization, Molecular Discovery Technologies, and Disease Sciences & Biology, Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543, United States.
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Traeger
authors.affiliation: Departments of Discovery Chemistry, Lead Discovery & Optimization, Preclinical Candidate Optimization, Molecular Discovery Technologies, and Disease Sciences & Biology, Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543, United States.
authors.forename: Songmei
authors.initials: S
authors.lastname: Xu
authors.affiliation: Departments of Discovery Chemistry, Lead Discovery & Optimization, Preclinical Candidate Optimization, Molecular Discovery Technologies, and Disease Sciences & Biology, Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543, United States.
authors.forename: Qihong
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: Departments of Discovery Chemistry, Lead Discovery & Optimization, Preclinical Candidate Optimization, Molecular Discovery Technologies, and Disease Sciences & Biology, Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543, United States.
authors.forename: Joel C
authors.initials: JC
authors.lastname: Barrish
keywords: Chemokine; GPCR; dual antagonist; inflammation