title: Rational design of potent and selective VLA-4 inhibitors and their utility in the treatment of asthma.
abstract: Asthma, a chronic inflammatory disease of the airways, is a significant burden on our healthcare system. There is high unmet need for treatments directed towards the underlying causes of the disease. The cell surface integrin VLA-4 (very late antigen-4; alpha4beta1; CD49d/CD29) plays an important role in the trafficking of white blood cells to sites of inflammation and represents an exciting target for the development of novel anti-inflammatory drugs for the treatment of asthma. Here, we review our efforts to use rational design to identify potent, selective inhibitors of VLA-4. We describe the discovery of a series of potent VLA-4 inhibitors through the addition of a novel N-terminal organic cap to a tetrapeptide VLA-4 binding motif 4-((N'-2-methylphenyl)uriedo)phenylacetyl-Leu-Asp-Val-Pro ; Kd = 70 pM), and rationalize their structure-activity relationships using 3D-QSAR. Also, we show our rational peptidomimetic design strategy using "template hopping" from the gpIIb/IIIa integrin antagonist field, and also a novel virtual screening strategy. Two series have been developed, one that has high selectivity for the activated over the non-activated state of the receptor, and the other which is non-selective inhibiting both activated and non-activated VLA-4. Both series are highly selective for VLA-4 versus against other integrin family members. These inhibitors show promise in the treatment of asthma, based upon efficacy in a sheep model of asthma, where they inhibit both the early and late-phase responses to asthma and also block hypersensitivity.
authors.affiliation: Biogen Idec, 12 Cambridge Center, Cambridge, MA 02142, USA. Juswinder.Singh@biogenidec.com
authors.forename: Juswinder
authors.initials: J
authors.lastname: Singh
authors.forename: Steve
authors.initials: S
authors.lastname: Adams
authors.forename: Mary Beth
authors.initials: MB
authors.lastname: Carter
authors.forename: Hernan
authors.initials: H
authors.lastname: Cuervo
authors.forename: Wen-Cherng
authors.initials: WC
authors.lastname: Lee
authors.forename: Roy R
authors.initials: RR
authors.lastname: Lobb
authors.forename: R Blake
authors.initials: RB
authors.lastname: Pepinsky
authors.forename: Russell
authors.initials: R
authors.lastname: Petter
authors.forename: Daniel
authors.initials: D
authors.lastname: Scott
mesh_terms: D000577:Amides / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001249:Asthma / Q000188:drug therapy*; D015195:Drug Design; D006801:Humans; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors*; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D039041:Integrin alpha4beta1; D010455:Peptides