Orally active, nonpeptide oxytocin antagonists

Evans, B.; Leighton, James L.; Rittle, Kenneth E.; Gilbert, Kevin F.; Lundell, G. F.; Gould, N. P.; Hobbs, Doug W.; DiPardo, Robert M.; Veber, Daniel F.; Pettibone, Douglas J.; Clineschmidt, Bradley V.; Anderson, Paul S.; Freidinger, Roger

doi:10.1021/jm00099a020

Cited by 83 publications

(42 citation statements)

References 5 publications

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“…The spiropiperidine part structure of this compound is a privileged structure in the terminology of Evans et al (11), since it is also found, for example, in oxytocin (15) and sigma receptor ligands (16). We derivatized the spiropiperidine core of 1 and from this approach lead compound 2 was discovered.…”

mentioning

confidence: 99%

Design and biological activities of L-163,191 (MK-0677): a potent, orally active growth hormone secretagogue.

Patchett

Nargund

Tata

et al. 1995

Proc. Natl. Acad. Sci. U.S.A.

314

201

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mentioning

confidence: 99%

Design and biological activities of L-163,191 (MK-0677): a potent, orally active growth hormone secretagogue.

Patchett

Nargund

Tata

et al. 1995

Proc. Natl. Acad. Sci. U.S.A.

314

201

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“…Spiro compounds are becoming key building blocks for drug discovery as these templates have been shown to exhibit a variety of interesting biological activities, such as growth hormone secretagogues (Ibutamoren, MK-0677) [1], neurokinin antagonists [2], oxytocin antagonists [3], monoamine transporter inhibitors [4], bradykinin antagonists [5] and cell cycle inhibitors [6]. Due to their structure, they interact with a wide range of receptors and this activity has resulted in significant interest in developing efficient methods to prepare spiro compounds.…”

Section: Introductionmentioning

confidence: 99%

An Efficient Synthesis of a Spirocyclic Oxindole Analogue

2006

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An efficient, scaleable synthesis approach towards the spirocyclic oxindole analogue 1'-(tert-butoxycarbonyl)-2-oxospiro[indoline-3,4'-piperidine]-5-carboxylic acid (1) is described. The key steps are dianion alkylation and cyclization of ethyl 2-oxindoline-5-carboxylate (4) and demethylation of the resulting spirocyclic oxindole ethyl 1'-methyl-2-oxospiro[indoline-3,4'-piperidine]-5-carboxylate (5). The target compound was obtained in an overall yield of 35 % over eight steps without resorting to chromatographic purification.

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“…These nonpeptidyl antagonists are represented by lead structures containing spiroindenylpiperidinecamphor-sulfonamide moieties (3,6,14). Further modification of these structures with potencyenhancing groups led to a group of potent, selective antagonists represented by Compounds I (L-368,899), II, and III ( Fig.…”

Section: Introductionmentioning

confidence: 99%

The Role of Drug Metabolism in Drug Discovery: A Case Study in the Selection of an Oxytocin Receptor Antagonist for Development

et al. 1995

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Drug discovery is a process involving multiple disciplines and interests. During the research phase of drug discovery, usually a large number of compounds are evaluated for biological activity and toxicological potential in animal species. Various types of problems with respect to pharmacodynamics, pharmacokinetics, and toxicity are commonly encountered at this stage. Drug metabolism, as a discipline participating in a drug discovery team, can play an important role in identifying factors underlying the problems, facilitate the optimal selection of compounds for further development, provide information on metabolites for possible improvement in drug design, and contribute to the identification of the appropriate animal species for subsequent toxicity testing. During the process of evaluating oxytocin receptor antagonists for further development for treatment of preterm labor, in vivo and in vitro drug metabolism studies conducted in rats, dogs, and monkeys contributed to the selection of L-368,899 as the development candidate on the basis of pharmacokinetic and metabolism observations. The presence of active N-demethylated metabolites of two other equipotent compounds in rats and dogs was found to be the major factor responsible for the discrepancy between oral bioavailability and efficacies observed for these 2 compounds. For L-368,899, a compound that demonstrated 20-40% oral bioavailability in rats, dogs, and chimpanzees, extensive first-pass metabolism rather than absorption was determined as the major factor responsible for the poor bioavailability (< 1%) in rhesus monkeys. In vitro metabolism studies with hepatic microsomes from rats, dogs, monkeys, and humans substantiated the conclusion that the rate of hepatic metabolism of L-368,899 in monkeys is faster than in the other species.

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Orally active, nonpeptide oxytocin antagonists

Cited by 83 publications

References 5 publications

Design and biological activities of L-163,191 (MK-0677): a potent, orally active growth hormone secretagogue.

Design and biological activities of L-163,191 (MK-0677): a potent, orally active growth hormone secretagogue.

An Efficient Synthesis of a Spirocyclic Oxindole Analogue

The Role of Drug Metabolism in Drug Discovery: A Case Study in the Selection of an Oxytocin Receptor Antagonist for Development

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