B1OORGAN1C & MEDICINAL CHEMISTRY LETTERS Pergamon Bioorganic & Medicinal Chemistry Letters 9 (1999) 2615-2620 IDENTIFICATION AND INITIAL STRUCTURE-ACTIVITY RELATIONSHIPS OF A NOVEL NON-PEPTIDE QUINOLONE GnRH RECEPTOR ANTAGONIST Robert J. DeVita, *a Darius D. Hollings, a Mark T. Goulet,a Matthew J. Wyvratt,a Michael H. Fisher,a Jane-L. Lo, b Yi Tien Yang, b Kang Chengb and Roy G. Smithb Departments of aMedicinal Chemistry and bBiochemistry and Physiology Merck Research Laboratories, P.O. Box 2000, Rahway, NJ 07065-0900, U.S.A. Received 23 June 1999; accepted 3 August 1999 Abstract: Screening of the Merck sample collection for non-peptide compounds with binding affinity for the rat GnRH receptor led to the identification of the substituted quinolone (1) as a lead compound in the search for a non-peptide GnRH receptor antagonist. Substantial improvements in potency (-300 fold) were achieved by addition of an alkyl amine at the 4-position, a 3,5-dimethylphenyl group at the 3-position and 6-nitro-7-chloro- substitution of the 1H-quinolone core. © 1999 E![sevier Science Ltd. All rights reserved. Introduction: Gonadotropin releasing hormone (GnRH), also known as luteinizing hormone-releasing hormone (LHRH), is a decapeptide released by the hypothalamus and identified in the early 1970's by Schally. 1 GnRH binds to gonadotropes in the pituitary activating the GnRH receptor, a G-protein coupled receptor, 2 causing the release of signaling hormones (FSH, LH) which act on the gonads to induce sex hormone production. A variety of disease conditions such as endometriosis and prostate cancer can be treated by suppression of the pituitary-gonad hormonal axis. Super agonists are used to over-stimulate the pituitary GnRH receptor which leads to down regulation of that receptor and shut down of the hormonal pathway. 3'4 The initial over production of sex hormones leads to an exacerbation of symptoms known as the "flare-effect." There is recent clinical evidence that peptidic GnRH antagonists directly lower sex hormone levels alleviating disease symptoms without the concomitant flare effect. 5 Peptidyl agonists and antagonists of the GnRH receptor have been used in the clinic for the treatment of sex hormone related conditions.6 A non-peptidyl GnRH receptor antagonist has been recently reported. 7 In this letter, we decribe the identification and initial structure-activity relationships of a novel lead structure for a non-peptidyl GnRH receptor antagonist. Lead Identification The search for a non-peptidyl GnRH receptor antagonist began with the development of an assay to identify compounds which bound competitively to GnRH receptors (from rat pituitary membranes) using a radio-labeled GnRH-agonist (125-1- buserelin). 8 Screening of the Merck sample collection led to the identification of the 4-(3-pyridylmethyl)oxyquinolone 1, prepared for an earlier project, 9 as an active (IC50 --- 10BM). After verifying the activity of the structure by re-synthesis and assay, we began a medicinal chemistry program to optimize the structure-activity relationships of this non-peptidyl lead compound. H 1 IC5o = 10gM 0960-894X/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved. PII: S0960-894X(99)00446-1