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S A Boyd A K Fung W R Baker R A Mantei Y L Armiger H H Stein J Cohen D A Egan J L Barlow V Klinghofer 《Journal of medicinal chemistry》1992,35(10):1735-1746
We describe the development of a series of soluble, potent, and bioavailable nonpeptide renin inhibitors. These inhibitors derived from a series of novel nonpeptide renin inhibitors which were recently identified in our laboratories, by alteration of the nature of the C-terminus (P2') of the molecules. Introduction of basic substituents into modified hydroxyethylene dipeptide isosteres gave inhibitors with improved solubility as well as improved potency against human plasma renin. In addition, these modifications produced inhibitors which displayed markedly improved intraduodenal bioavailability in both the ferret and cynomolgus monkey. We also present data which demonstrate excellent efficacy in the monkey for A-74273 (65), with an intraduodenal bioavailability of 16 +/- 4% in the monkey, compared to 1.7 +/- 0.5% for the dipeptide renin inhibitor enalkiren (A-64662, 75). A-74273 is an example of a nonpeptide inhibitor which possesses a good balance of the desirable properties of potency, solubility, and lipophilicity and which is well absorbed into the intestine. 相似文献
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Bals-Pratsch M; De Geyter C; Muller T; Frieling U; Lerchl A; Pirke KM; Hanker JP; Becker-Carus C; Nieschlag E 《Human reproduction (Oxford, England)》1997,12(5):896-904
Preliminary data have suggested that female infertility due to corpus
luteum insufficiency may be caused by subclinical hypothyroidism
[exaggerated thyroid-stimulating hormone (TSH) response to thyrotrophin-
releasing hormone (TRH) stimulation]. L-Thyroxine supplementation has been
recommended to achieve pregnancies in subclinical hypothyroid women. This
controlled study was carried out in order to investigate the biochemical
diagnosis of subclinical hypothyroidism as a possible infertility factor.
Five infertile patients (aged 25-36 years) with subclinical hypothyroidism
(n = 4, stimulated TSH >20 microU/ml) or primary hypothyroidism (n = 1)
and five healthy controls (aged 22-39 years) with normal thyroid function
(stimulated TSH <15 microU/ml), regular cycles and no history of
infertility were studied in the early follicular phase. In the pre-study
evaluation, eight of 23 volunteers (34.8%) had to be excluded because of
subclinical hypothyroidism with stimulated TSH values (TSHs) >15
microU/ml. Cycle function of patients and controls was compared by the
method of LH pulse pattern analysis. Therefore blood samples were drawn
every 10 min during a 24 h period. Sleep was recorded from midnight to 7
a.m. Repetition of the TRH tests at the end of the 24 h blood sampling
period confirmed the difference in stimulated TSH values of the two study
groups. Pulse analysis for luteinizing hormone (LH), TSH and prolactin
showed no differences between patients and controls for pulse frequency,
amplitude, height, length, area under curve (AUC) and the 24 h mean. Even
the hypothyroid patient had a normal LH pulse pattern. Additional
measurement of melatonin in pooled sera every 30 min gave the
well-documented diurnal profiles during day and night for both groups.
Patients had significantly higher melatonin values at seven time points
during the night. Peaks for LH, TSH, prolactin and cortisol were correlated
with the sleep stages wake, rapid eye movement, 1 + 2 and 3 + 4. We
concluded that corpus luteum insufficiency in female infertility cannot be
explained by subclinical hypothyroidism and thus should not be treated with
L-thyroxine for fertility reasons.
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