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Frederick T. Becker

Bio: Frederick T. Becker is an academic researcher from Schering-Plough. The author has contributed to research in topics: Angiotensin-converting enzyme & Clonidine. The author has an hindex of 4, co-authored 8 publications receiving 85 citations.

Papers
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Journal ArticleDOI
TL;DR: Data indicate that SCH 31846 is a potent and specific non-sulfhydryl ACE inhibitor, which should be useful in the treatment of hypertension and heart failure.
Abstract: SCH 31846, 1-(N-[1(S)-(ethoxycarbonyl)-3-phenylpropyl]-(S)-alanyl)-cis, syn-octahydro-(H-indole-2-S)-carboxylic acid; CI-907; PD 109, 763-2, is a new non-sulfhydryl-containing, angiotensin-converting enzyme (ACE) inhibitor. The present investigation describes its ACE inhibitory properties and compares them to those of MK 421. The diacid of SCH 31846 inhibited rabbit pulmonary ACE with an IC50 of 2.2 nM (MK 421 diacid 2.5 nM). The drug behaved as a competitive and specific inhibitor in vitro. SCH 31846 and its diacid effectively inhibited pressor actions of intravenous injection of angiotensin I (AI) in anesthetized rats. ID50 values were 27 and 11 micrograms/kg for SCH 31846 and SCH 31846 diacid, respectively (MK 421 and MK 421 diacid 57 and 15 micrograms/kg, respectively). Oral administration of SCH 31846 (0.03-1 mg/kg) inhibited pressor actions of AI in conscious rats with a duration of over 16 h at 0.3 and 1 mg/kg. SCH 31846 was 2.2 times as potent as MK 421 in this regard. The diacid of SCH 31846 was considerably less potent than the ester, implying poor oral absorption of the former. Effective ACE inhibition, as judged by attenuation of pressor actions of AI, was noted in dogs after both intravenous and oral administrations of SCH 31846. Onset of action was more rapid than that of MK 421. Intravenous administration of SCH 31846 inhibited the renal vascular actions of intrarenal injection of AI, indicating effective blockade of the renal enzyme. Intracerebroventricular administration of SCH 31846 diacid blocked pressor responses to intracerebroventricular AI, whereas oral administration of SCH 31846 (10 mg/kg) did not, implying that SCH 31846 inhibits brain ACE but does not gain access to the cerebral enzyme when administered orally. These data indicate that SCH 31846 is a potent and specific non-sulfhydryl ACE inhibitor. As such, it should be useful in the treatment of hypertension and heart failure.

24 citations

Journal ArticleDOI
TL;DR: It is concluded that SCH 31846 is a potent and long-lasting antihypertensive agent, the action of which is mediated, in all probability, by ACE inhibition.
Abstract: The antihypertensive, hemodynamic, and autonomic actions of SCH 31846, a new, potent and long-acting non-sulfhydryl angiotensin-converting enzyme (ACE) inhibitor, were evaluated in several experimental preparations. Oral administration of 0.3-3 mg/kg caused dose-related decreases in blood pressure in spontaneously hypertensive rats (SHRs). Pretreatment with a diuretic augmented the maximum hypotensive response attainable. Single doses (3 mg/kg) of SCH 31846 reduced pressure for over 24 h. Five-day treatment lowered pressure progressively. Single oral doses of 3.2 and 10 mg/kg reduced blood pressure of conscious normotensive dogs. Diuretic pretreatment also enhanced the response. The antihypertensive action of SCH 31846 in SHRs was eliminated by nephrectomy, but not attenuated by indomethacin, indicating its dependency on renal renin but not on prostaglandin synthesis. Other studies using SHRs pointed to an absence of a central effect. SCH 31846 (1 mg/kg i.v.) decreased blood pressure and peripheral resistance of anesthetized dogs but did not alter cardiac output. Autonomic interactions were examined in normal and diuretic-pretreated SHRs and anesthetized dogs. SCH 31846 affected the response to sympathetic nerve stimulation and cardiovascular reflexes only minimally. It is concluded that SCH 31846 is a potent and long-lasting antihypertensive agent, the action of which is mediated, in all probability, by ACE inhibition.

20 citations

Journal ArticleDOI
TL;DR: It is indicated that MK 421 and captopril can inhibit brain ACE but that the central renin-angiotensin system probably does not contribute to their antihypertensive activity.

17 citations

Journal ArticleDOI
TL;DR: The present series of experiments examined the effects of thiorphan, an inhibitor of enkephalinase A, on cardiovascular responses to intracerebroventricular (i.c.v.) administration of DAME and its amide and on peripheral interactions with the sympathetic nervous system and vasoactive peptides.

12 citations

Journal Article
TL;DR: SCH 33844 is a potent, orally effective ACE inhibitor in rats, dogs and monkeys and potentiated the depressor response to bradykinin.
Abstract: SCH 33844 is a new non-sulfhydryl-containing angiotensin converting enzyme (ACE) inhibitor. SCH 33844 diacid inhibited hydrolysis of the synthetic substrate hippuryl-histidyl-leucine by rabbit lung ACE in vitro with an IC50 (concentration inhibiting enzyme by 50%) of 0.81 nM. The ester was 83 times less active. Intravenous administration of SCH 33844 and its diacid inhibited pressor responses to angiotensin I (AI) in anesthetized rats with calculated ID50's of 16 and 8 micrograms/kg, respectively. Oral administration of SCH 33844 (0.03-1 mg/kg) inhibited AI pressor responses in conscious rats with a duration of 24 hr at the highest dose. The diacid was inactive. Intravenous administration of SCH 33844 (100-1000 micrograms/kg) or its diacid (30 micrograms/kg) to anesthetized dogs inhibited AI pressor activity and potentiated the depressor response to bradykinin. SCH 33844 inhibited AI responses in conscious dogs following oral administration of 0.3-3 mg/kg. Oral administration of SCH 33844 (1 mg/kg) to conscious monkeys inhibited AI pressor responses for the 4 hr duration of study. In conclusion, SCH 33844 is a potent, orally effective ACE inhibitor in rats, dogs and monkeys.

4 citations


Cited by
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Journal ArticleDOI
01 Mar 1986-Drugs
TL;DR: Enalapril 10 to 40 mg/day administered either once or twice daily is effective in lowering blood pressure in all grades of essential and renovascular hypertension, and shows similar efficacy to usual therapeutic dosages of hydrochlorothiazide, beta-blockers and captopril.
Abstract: Captopril is an orally active inhibitor of angiotensin-converting enzyme (ACE) and has been widely studied in the treatment of patients with mild to moderate essential hypertension, severe hypertension not responsive to conventional diuretic/beta-adrenoceptor blocker/vasodilator regimens, and patients with chronic congestive heart failure refractory to treatment with a diuretic and digitalis. In patients with mild or moderate essential hypertension, titrated low doses of captopril used alone or in conjunction with a diuretic are similar in efficacy to usual doses of hydrochlorothiazide, chlorthalidone, or beta-adrenoceptor blocking drugs, as well as to the other ACE inhibitors. In addition, captopril improved well-being to a greater extent than methyldopa or propranolol in a study designed specifically to determine the effect of treatment on the quality of life of patients with mild or moderate essential hypertension. The earlier demonstrated efficacy of captopril, used with a diuretic and often also with a beta-adrenoceptor blocking drug, in the treatment of severe hypertension refractory to conventional 'triple therapy' has been confirmed in more recent trials which illustrate the generally marked antihypertensive effect of captopril-containing regimens in such patients. Results of initial trials in patients with scleroderma are promising, with control of hypertension and stabilization of renal function in these patients when treated at an early stage of the disease. Several comparative and long term trials of captopril in patients with chronic congestive heart failure refractory to treatment with a diuretic/digitalis regimen clearly demonstrate that initial haemodynamic improvement is maintained and correlates with clinical benefit. A tendency for overall clinical response to captopril to be better than the response to prazosin, hydralazine, nisoldipine or enalapril has been reported. Results of a multicentre comparison with digoxin and placebo indicate that captopril is a suitable alternative to digoxin in patients with mild to moderate heart failure who are receiving maintenance diuretic therapy. The tolerability of captopril has now been studied in many thousands of patients involved in formalized trials and the early impression of poor tolerability can no longer be justified. The use of generally lower dosages of captopril in patients with normal or slightly impaired renal function has resulted in a generally low incidence of rash (0.5 to 4%), dysgeusia (0.1 to 3%), proteinuria (0.5%), neutropenia (0.3% during first 3 months) and symptomatic hypotension (0.1 to 3%). Cough is an infrequent but troublesome effect resulting from ACE inhibition.(ABSTRACT TRUNCATED AT 400 WORDS)

362 citations

Journal Article
T Unger1, E. Badoer, Detlev Ganten, R E Lang, R Rettig 
TL;DR: Evidence from biochemical, neurophysiologic, pharmacologic, and most recently, molecular genetic studies indicate that the brain RAS is regulated independently of the hormonal RAS and may contribute to blood pressure control and body fluid homeostasis.
Abstract: The existence of a brain renin-angiotensin system (RAS) as one of various tissue RASs is now firmly established. Angiotensin-containing pathways within brain areas involved in central blood pressure regulation have been described. Evidence from biochemical, neurophysiologic, pharmacologic, and most recently, molecular genetic studies indicate that the brain RAS is regulated independently of the hormonal RAS and may contribute to blood pressure control and body fluid homeostasis. In addition, circulating angiotensin II can exert some of its action through stimulation of brain angiotensin receptors accessible from the blood. In experimental animal preparations of hypertension, especially in spontaneously hypertensive rats, an overactive brain RAS may be one of the factors involved in pathogenesis and maintenance of hypertension. In spontaneously hypertensive rats, inhibitors of the angiotensin II-generating converting enzyme (CE) have been shown to lower blood pressure by a central action when applied to the brain and to inhibit brain CE when applied systemically. The pathogenetic mechanisms underlying a particular cardiovascular disease and the characteristics of the CE inhibitor used (e.g., its lipid solubility governing penetration into tissue) may determine the degree to which CE inhibition within a given organ, such as the brain, contributes to the action of these drugs.

249 citations

Journal ArticleDOI
TL;DR: It is hoped that some of the insights to be derived from the SAR and structural studies done with ACE inhibitors will be applicable to other enzyme targets as well.
Abstract: Orally-active angiotensin-converting enzyme inhibitors are rapidly establishing themselves in the therapy of hypertension and congestive heart failure. Concerted efforts in a number of laboratories have now led to the discovery or synthesis of an unparalleled variety of potent inhibitors. The manner in which several of these inhibitors bind to ACE is beginning to be understood. It is hoped that some of the insights to be derived from the SAR and structural studies done with ACE inhibitors will be applicable to other enzyme targets as well. The success of ACE inhibitors as pharmacological tools and in the clinic will also quite certainly encourage future efforts to develop new enzyme inhibitor approaches to drug therapy.

246 citations

Patent
17 Jun 1987
TL;DR: In this article, the method of treating hypertension with neutral metalloendopeptidase (NMEP) inhibitors, NMEP inhibitors in combination with atrial peptides, and NMEP inhibitor in combination of angiotensin converting enzyme inhibitors, as well as pharmaceutical compositions therefor, are disclosed.
Abstract: The method of treating hypertension with neutral metalloendopeptidase (NMEP) inhibitors, NMEP inhibitors in combination with atrial peptides, and NMEP inhibitors in combination with angiotensin converting enzyme inhibitors, as well as pharmaceutical compositions therefor, are disclosed.

97 citations

Journal ArticleDOI
TL;DR: It is surmised that the therapeutic effects of converting enzyme inhibitors are, in part, brought about by inhibition of local tissue angiotensin II generation in addition to their interference with the hormonal plasma renin-angiotensIn system.

86 citations