Role of nonhuman primate models in the discovery and clinical development of selective progesterone receptor modulators (SPRMs).
Selective progesterone receptor modulators (SPRMs) represent a new class of progesterone receptor ligands that exert clinically relevant tissue-selective progesterone agonist, antagonist, partial, or mixed agonist/antagonist effects on various progesterone target tissues in an in vivo situation depending on the biological action studied. The SPRM asoprisnil is being studied in women with symptomatic uterine leiomyomata and endometriosis. Asoprisnil shows a high degree of uterine selectivity as compared to effects on ovulation or ovarian hormone secretion in humans. It induces amenorrhea and decreases leiomyoma volume in a dose-dependent manner in the presence of follicular phase estrogen concentrations. It also has endometrial antiproliferative effects. In pregnant animals, the myometrial, i.e. labor-inducing, effects of asoprisnil are blunted or absent. Studies in non-human primates played a key role during the preclinical development of selective progesterone receptor modulators. These studies provided the first evidence of uterus-selective effects of asoprisnil and structurally related compounds, and the rationale for clinical development of asoprisnil.
Chwalisz
Kristof
K
TAP Pharmaceutical Products Inc, Lake Forest, Illinois, USA. Kristof.Chwalisz@TAP.com
Garg
Ramesh
R
Brenner
Robert
R
Slayden
Ov
O
Winkel
Craig
C
Elger
Walter
W
D000818:Animals; D004353:Drug Evaluation, Preclinical; D004717:Endometrium / Q000187:drug effects; D004963:Estrenes / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D006801:Humans; D007889:Leiomyoma / Q000188:drug therapy; D008321:Mammary Glands, Animal / Q000187:drug effects; D023421:Models, Animal; D008954:Models, Biological; D008958:Models, Molecular; D009928:Organ Specificity; D010091:Oximes / Q000737:chemistry / Q000494:pharmacology; D011323:Primates / Q000502:physiology*; D045167:Progesterone Congeners / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use*; D011980:Receptors, Progesterone / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014592:Uterine Hemorrhage / Q000188:drug therapy; D014594:Uterine Neoplasms / Q000188:drug therapy; D014599:Uterus / Q000187:drug effects
D004963:Estrenes; D010091:Oximes; D045167:Progesterone Congeners; D011980:Receptors, Progesterone; C488516:asoprisnil