N-(arylacetyl)-biphenylalanines as potent VLA-4 antagonists

Bing Li; Stephen E de Laszlo; Theodore M Kamenecka; Ihor E Kopka; Philippe L Durette; Thomas Lanza Jr; Malcolm MacCoss; Sharon Tong; Richard A Mumford; Ermengilda D McCauley; Gail Van Riper; John A Schmidt; William K Hagmann

doi:10.1016/s0960-894x(02)00366-9

N-(arylacetyl)-biphenylalanines as potent VLA-4 antagonists

Bioorg Med Chem Lett. 2002 Aug 19;12(16):2141-4. doi: 10.1016/s0960-894x(02)00366-9.

Authors

Bing Li¹, Stephen E de Laszlo, Theodore M Kamenecka, Ihor E Kopka, Philippe L Durette, Thomas Lanza Jr, Malcolm MacCoss, Sharon Tong, Richard A Mumford, Ermengilda D McCauley, Gail Van Riper, John A Schmidt, William K Hagmann

Affiliation

¹ Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. [email protected]

PMID: 12127523
DOI: 10.1016/s0960-894x(02)00366-9

Abstract

A series of potent N-(aralkyl-, arylcycloalkyl-, and heteroaryl-acyl)-4-biphenylalanine VLA-4 antagonists was prepared by rapid analogue methods using solid-phase chemistry. Further optimization led to several highly potent compounds (IC(50) <1 nM). Evaluation of rat pharmacokinetic revealed generally high clearance.

MeSH terms

Animals
Binding Sites
Inhibitory Concentration 50
Integrin alpha4beta1 / antagonists & inhibitors*
Molecular Structure
Phenylalanine / analogs & derivatives
Phenylalanine / chemical synthesis*
Phenylalanine / pharmacokinetics
Phenylalanine / pharmacology*
Rats
Structure-Activity Relationship

Substances

Integrin alpha4beta1
Phenylalanine