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.
Lin
Linus S
LS
Department of Medicinal Chemistry, Immunology and Rheumatology, and Drug Metabolism, Merck Research Laboratories, Rahway, NJ 07065, USA. linus_lin@merck.com
Lanza
Thomas
T
Jewell
James P
JP
Liu
Ping
P
Jones
Carrie
C
Kieczykowski
Gerard R
GR
Treonze
Kelly
K
Si
Qian
Q
Manior
Salony
S
Koo
Gloria
G
Tong
Xinchun
X
Wang
Junying
J
Schuelke
Anne
A
Pivnichny
James
J
Wang
Regina
R
Raab
Conrad
C
Vincent
Stella
S
Davies
Philip
P
Maccoss
Malcolm
M
Mumford
Richard A
RA
Hagmann
William K
WK
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