Azido glycols: potent, low molecular weight renin inhibitors containing an unusual post scissile site residue

Sh, Rosenberg; Kw, Woods; Hd, Kleinert; Stein, Herman H.; Hn, Nellans; Dj, Hoffman; Sg, Spanton; Ra, Pyter; Cohen, Jerome; Egan, Deirdre

doi:10.1021/jm00126a038

Cited by 18 publications

(4 citation statements)

References 3 publications

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“…We have evaluated the intestinal absorption of compounds 15a-g and 16a-i using the id rat model developed previously to evaluate a series of renin inhibitors. 11 Briefly, blood samples are collected from the portal vein of an anesthetized rat at several time points after the test compound is injected into its duodenum. Plasma drug levels are quantitated using an HPLC-based assay after the samples have undergone organic extraction.…”

Section: Pharmacokinetic Studiesmentioning

confidence: 99%

Azole Endothelin Antagonists. 3. Using Δ log P as a Tool To Improve Absorption

et al. 1996

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The oral absorption profile of a family of azole-based ET(A)-selective antagonists has been improved through a rational series of structural modifications which were suggested by analysis of the physicochemical parameter delta log P. Comparison of urea 2 with a series of well-absorbed compounds using delta log P analysis suggested that 2 has an excess capacity for forming hydrogen bonds with solvent. A series of urea modifications were explored as a means of reducing H-bonding capacity while maintaining affinity for the ET(A)-receptor. The correlation between delta log P values and absorption in an intraduodenal (id) bioavailability model was good; this strategy uncovered replacements for each of the urea NH groups which simultaneously improve both potency and drug absorption. A combination of these optimized modifications produces carbamate 16h, a highly-selective ET(A) antagonist with a potency/bioavailability profile consistent with an oral route of administration.

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Section: Pharmacokinetic Studiesmentioning

confidence: 99%

Azole Endothelin Antagonists. 3. Using Δ log P as a Tool To Improve Absorption

et al. 1996

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“…Chromatography of the residue with 1.3-1.5% methanol in chloroform afforded 0.57 g (81%) of an oil: TLC (V) Rf = 0.15, (VI) Rf = 0.57; TO NMR (CDC13) 8 8.57-8.43 (m, 1H), 7.63-7.51 (m, 1H), 7.38-6.98 (m, 12 H), 5.20-5.00 (4 d, total 2 H), 3.80-3.52 (m, 2 H), 3.38-3.18 (m, 1H), 3.08-2.57 (envelope, 5 H), 2.86,2.82 (2 s, total 3 H), 2.30, 2.18 (2 dd, total 1 H); MS m/e (M + H)+ 417.…”

Section: Methodsmentioning

confidence: 99%

Studies directed toward the design of orally active renin inhibitors. 2. Development of the efficacious, bioavailable renin inhibitor (2S)-2-benzyl-3-[[(1-methylpiperazin-4-yl)sulfonyl]propionyl]-3-thiazol-4-yl-L-alanine amide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane (A-72517)

Rosenberg¹,

Spina²,

Condon³

et al. 1993

J. Med. Chem.

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Employing a set of empirical guidelines for the design of well-absorbed renin inhibitors, we have followed two strategies to improve potency while maintaining bioavailability. One process involved incorporation of an extended N-terminal residue bearing a weakly basic substituent and is exemplified by compound 25. The other approach centered on the inclusion of an N-terminal sulfonamide and culminated in the discovery of inhibitor 32 (A-72517). Both 25 and 32 showed excellent bioavailability in the rat and ferret (> 25%) and, while subject to hepatic elimination in the monkey, were efficacious in this species.

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“…The studies of the structure, effectiveness and bioavailability of zanikiren were conducted on various animal species like dogs, rats, monkeys and ferrets. The obtained results were widely presented in the papers of Rosenberg et al 50,51 and Kleinert et al 52 In case of determination of the examined substance and its metabolites in serum, the authors used a direct method, such as high-performance liquid chromatography, 50,52 or indirect methods involving renin inhibition assays 51 or plasma renin activity determination. 53 Two procedures were used in case of the HPLC method.…”

Section: Zanikirenmentioning

confidence: 99%