title: Synthesis and SAR of N-benzoyl-L-biphenylalanine derivatives: discovery of TR-14035, a dual alpha(4)beta(7)/alpha(4)beta(1) integrin antagonist.
abstract: alpha(4)beta(1) and alpha(4)beta(7) integrins are key regulators of physiologic and pathologic responses in inflammation and autoimmune disease. The effectiveness of anti-integrin antibodies to attenuate a number of inflammatory/immune conditions provides a strong rationale to target integrins for drug development. Important advances have been made in identifying potent and selective candidates, peptides and peptidomimetics, for further development. Herein, we report the discovery of a series of novel N-benzoyl-L-biphenylalanine derivatives that are potent inhibitors of alpha4 integrins. The potency of the initial lead compound (1: IC(50) alpha(4)beta(7)/alpha(4)beta(1)=5/33 microM) was optimized via sequential manipulation of substituents to generate low nM, orally bioavailable dual alpha(4)beta(1)/alpha(4)beta(7) antagonists. The SAR also led to the identification of several subnanomolar antagonists (134, 142, and 143). Compound 81 (TR-14035; IC(50) alpha(4)beta(7)/alpha(4)beta(1)=7/87 nM) has completed Phase I studies in Europe. The synthesis, SAR and biological evaluation of these compounds are described.
authors.affiliation: Department of Chemical Science, Tanabe Research Laboratories, USA, Inc., 4540 Towne Centre Court, San Diego, CA 92121, USA. sircar@trlusa.com
authors.forename: Ila
authors.initials: I
authors.lastname: Sircar
authors.forename: Kristjan S
authors.initials: KS
authors.lastname: Gudmundsson
authors.forename: Richard
authors.initials: R
authors.lastname: Martin
authors.forename: Jimmy
authors.initials: J
authors.lastname: Liang
authors.forename: Sumihiro
authors.initials: S
authors.lastname: Nomura
authors.forename: Honnappa
authors.initials: H
authors.lastname: Jayakumar
authors.forename: Bradley R
authors.initials: BR
authors.lastname: Teegarden
authors.forename: Dawn M
authors.initials: DM
authors.lastname: Nowlin
authors.forename: Pina M
authors.initials: PM
authors.lastname: Cardarelli
authors.forename: Jason R
authors.initials: JR
authors.lastname: Mah
authors.forename: Samuel
authors.initials: S
authors.lastname: Connell
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Griffith
authors.forename: Elias
authors.initials: E
authors.lastname: Lazarides
mesh_terms: D002448:Cell Adhesion / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors*; D016023:Integrins / Q000037:antagonists & inhibitors*; D019169:Jurkat Cells; D015394:Molecular Structure; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D039041:Integrin alpha4beta1; D016023:Integrins; C459380:N-(2,6-dichlorobenzoyl)-4-(2',6'-bismethoxyphenyl)phenylalanine; C071777:integrin alpha4beta7; D010649:Phenylalanine