Application of structure–metabolism relationships in the identification of a selective endothelin A antagonist, BMS-193884, with favourable pharmacokinetic properties

W. G. Humphreys Department of Metabolism and Pharmacokinetics, Preclinical Candidate Optimization, PO Box 5400, Princeton, NJ, 08543, USA; Department of Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 5400, Princeton, NJ, 08543, USACorrespondence[email protected]

M. T. Obermeier Department of Metabolism and Pharmacokinetics, Preclinical Candidate Optimization, PO Box 5400, Princeton, NJ, 08543, USA; Department of Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 5400, Princeton, NJ, 08543, USA

J. C. Barrish Department of Metabolism and Pharmacokinetics, Preclinical Candidate Optimization, PO Box 5400, Princeton, NJ, 08543, USA; Department of Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 5400, Princeton, NJ, 08543, USA

S. Chong Department of Metabolism and Pharmacokinetics, Preclinical Candidate Optimization, PO Box 5400, Princeton, NJ, 08543, USA; Department of Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 5400, Princeton, NJ, 08543, USA

A. M. Marino Department of Metabolism and Pharmacokinetics, Preclinical Candidate Optimization, PO Box 5400, Princeton, NJ, 08543, USA; Department of Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 5400, Princeton, NJ, 08543, USA

N. Murugesan Department of Metabolism and Pharmacokinetics, Preclinical Candidate Optimization, PO Box 5400, Princeton, NJ, 08543, USA; Department of Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 5400, Princeton, NJ, 08543, USA

D. Wang-Iverson Department of Metabolism and Pharmacokinetics, Preclinical Candidate Optimization, PO Box 5400, Princeton, NJ, 08543, USA; Department of Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 5400, Princeton, NJ, 08543, USA

R. A. Morrison Department of Metabolism and Pharmacokinetics, Preclinical Candidate Optimization, PO Box 5400, Princeton, NJ, 08543, USA; Department of Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 5400, Princeton, NJ, 08543, USA

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Abstract

1. Based on binding affinity, 2′-amino-N-(3,4-dimethyl-5-isoxazolyl)-4′-(2-methylpropyl)[1,1′-biphenyl]-2-sulfonamide (2) was identified as an initial lead in a programme to identify selective endothelin (ET) receptor antagonists. However, the compound was extensively metabolized in preclinical animal species and human in vitro systems due to oxidative biotransformation.

2. To optimize this structural class, the site of metabolism of 2 was determined. This allowed for focussed structure–activity and structure–metabolism studies aimed at finding more metabolically stable analogues that maintained potency. New analogues were screened for their ET binding characteristics and their stability in rat and human liver microsomes.

3. The use of the microsomal stability screen was tested by the determination of the pharmacokinetic parameters of select analogues. A good correlation was found between reduced rates of rat microsomal metabolism and reduced clearance in the rat.

4. N-(3,4-dimethyl-5-isoxazolyl)-4′-(2-oxazolyl)[1,1′-biphenyl]-2-sulfonamide (3) was identified as an analogue with improved in vitro properties and further studies revealed that the compound had improved pharmacokinetic properties.

5. N-[[2′-[[(3,4-dimethyl-5-isoxazolyl)amino]sulfonyl]-4-(2-oxazolyl)[1,1′-biphenyl]-2-yl]methyl]acetamide (4) was subsequently identified as a compound with superior in vitro properties compared with compound 3, but when tested in vivo it had a substantially increased rate of clearance. Further studies demonstrated that the clearance of this closely related structural analogue was not dictated by metabolic processes, but was mediated by transport-mediated direct biliary excretion.

6. The utility of screening for in vitro liver microsomal stability as part of the lead optimization process for compounds with metabolic liabilities was shown. It was also shown that relatively small molecular changes can dramatically change the disposition of closely related analogues and care must be used when screening for a single property.

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Application of structure–metabolism relationships in the identification of a selective endothelin A antagonist, BMS-193884, with favourable pharmacokinetic properties

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Application of structure–metabolism relationships in the identification of a selective endothelin A antagonist, BMS-193884, with favourable pharmacokinetic properties

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