Discovery of N-{N-[(3-cyanophenyl)sulfonyl]-4(R)-cyclobutylamino-(L)-prolyl}-4-[(3',5'-dichloroisonicotinoyl) amino]-(L)-phenylalanine (MK-0668), an extremely potent and orally active antagonist of very late antigen-4.
Extremely potent very late antigen-4 (VLA-4) antagonists with picomolar, whole blood activity and slow dissociation rates were discovered by incorporating an amino substituent on the proline fragment of the initial lead structure. This level of potency against the unactivated form of VLA-4 was shown to be sufficient to overcome the poor pharmacokinetic profiles typical of this class of VLA-4 antagonists, and sustained activity as measured by receptor occupancy was achieved in preclinical species after oral dosing.
Department of Medicinal Chemistry, Immunology and Rheumatology, and Drug Metabolism, Merck Research Laboratories, Rahway, NJ 07065, USA. linus_lin@merck.com
Linus S
LS
Lin
Thomas
T
Lanza
James P
JP
Jewell
Ping
P
Liu
Carrie
C
Jones
Gerard R
GR
Kieczykowski
Kelly
K
Treonze
Qian
Q
Si
Salony
S
Manior
Gloria
G
Koo
Xinchun
X
Tong
Junying
J
Wang
Anne
A
Schuelke
James
J
Pivnichny
Regina
R
Wang
Conrad
C
Raab
Stella
S
Vincent
Philip
P
Davies
Malcolm
M
Maccoss
Richard A
RA
Mumford
William K
WK
Hagmann
D000284:Administration, Oral; D000818:Animals; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D004285:Dogs; D006801:Humans; D020128:Inhibitory Concentration 50; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors*; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D010649:Phenylalanine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats
D065692:Cytochrome P-450 CYP3A Inhibitors; D039041:Integrin alpha4beta1; C541700:N-(N-((3-cyanophenyl)sulfonyl)-4-cyclobutylaminoprolyl)-4-((3',5'-dichloroisonicotinoyl)amino)phenylalanine; D009536:Niacinamide; D010649:Phenylalanine; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human