Conformationally constrained o-tolylpiperazine camphorsulfonamide oxytocin antagonists. Structural modifications that provide high receptor affinity and suggest a bioactive conformation.
A series of new o-tolylpiperazine camphorsulfonamide OT antagonists is described. Analogs containing conformationally constrained 1-acylamino-2-propyl substituents at the camphor C2 endo position exhibit high affinity for OT and AVP-V1a receptors or high affinity and selectivity for OT receptors, depending on functionalities present in the acyl group. Determination of the preferred conformation of potency-enhancing 1-acylamino-2-propyl substituents using molecular mechanics energy calculations and X-ray crystallography, along with topological similarities to a conformationally constrained cyclic hexapeptide OT antagonist, suggests a receptor-bound conformation for this series of non-peptide OT antagonists.
Williams
P D
PD
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486.
Ball
R G
RG
Clineschmidt
B V
BV
Culberson
J C
JC
Erb
J M
JM
Freidinger
R M
RM
Pawluczyk
J M
JM
Perlow
D S
DS
Pettibone
D J
DJ
Veber
D F
DF
D000595:Amino Acid Sequence; D000818:Animals; D002164:Camphor / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D006801:Humans; D007668:Kidney / Q000378:metabolism; D007700:Kinetics; D008099:Liver / Q000378:metabolism; D008297:Male; D008958:Models, Molecular; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D010121:Oxytocin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D018045:Receptors, Oxytocin / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D017483:Receptors, Vasopressin / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D014316:Tritium; D014590:Uterine Contraction / Q000187:drug effects; D014599:Uterus / Q000378:metabolism
D010879:Piperazines; D018045:Receptors, Oxytocin; D017483:Receptors, Vasopressin; D013449:Sulfonamides; D014316:Tritium; D010121:Oxytocin; D002164:Camphor