Neurokinin-3 receptor (NK3R) has recently emerged as important in modulating the tonic pulsatile gonadotropin-releasing hormone (GnRH) release. We therefore decided to explore NK3R antagonists as therapeutics for sex-hormone disorders that can potentially benefit from lowering GnRH pulsatility with consequent diminished levels of plasma luteinizing hormone (LH) and correspondingly attenuated levels of circulating androgens and estrogens. The discovery and lead optimization of a novel N-acyl-triazolopiperazine NK3R antagonist chemotype achieved through bioisosteric lead change from the high-throughput screening (HTS) hit is described. A concomitant improvement in the antagonist bioactivity and ligand lipophilic efficiency (LLE) parameter were the principal guidelines in the lead optimization efforts. Examples of advanced lead analogues to demonstrate the amenability of this chemotype to achieving a suitable pharmacokinetic (PK) profile are provided as well as pharmacokinetic-pharmacodynamic (PKPD) correlations to analyze the trends observed for LH inhibition in castrated rats and monkeys that served as preliminary in vivo efficacy models.

The synthesis of a potential key intermediate for the synthesis of the 4,19‐diol derivative of (–)‐mycothiazole using convergent strategies is described in this paper. Several approaches have been tested, including cross metathesis and a Julia–Kocienski olefination. Finally, the formation of the 1,1‐dialkyl‐1,2‐ethanediol motif through C4–C5 bond construction was realized by nucleophilic addition of a vinyl iodide derivative to a keto ester after halogen/lithium exchange followed by reduction of the resulting hydroxy ester.

A single addition of the catalyst, Pd(OAc)(2), was realised to mediate two transformations as different as allylic alcohol oxidation under O(2) and C-C bond formation of the Heck type, to give substituted alpha,beta-unsaturated ketones without intermediate purification.

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Allylic alcohols were selectively oxidized into aldehydes or ketones using a Pd(OAc) 2 -Et 3 N-O 2 system. Diols with one allylic function were selectively oxidized, with one of the hydroxyl groups remaining untouched.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Hydroxylation O 0216 Unexpected Tosyl Deprotection During Osmium Catalyzed Dihydroxylation. -Depending on the position of the double bond, the olefins undergo unexpected detosylation. The structurally related mesylate (V) is also deprotected, whereas the tosylamide (VI) is not. -(BATT, F.; PIVA, O.; FACHE*, F.; Tetrahedron Lett. 49 (2008) 3, 566-568; Lab. Chim. Org. Photochim. Synth., CNRS, Univ. Claude Bernard Lyon, F-69622 Villeurbanne, Fr.; Eng.) -Mais 18-035