Biomedical subjects
Publications and source records attributed to B E Abboa-Offei.
A series of N-(4-hydroxy-3-methylsulfonanilidoethanol)arylglycinamides were prepared and evaluated for their human beta3 adrenergic receptor agonist activity. SAR studies led to the identification of BMS-201620 (39), a potent beta3 full agonist (Ki = 93 nM, 93% activation). Based on its favorable safety profile, BMS-201620 was chosen for clinical evaluation.
Screening of the BMS collection identified 4-hydroxy-3-methylsulfonanilidoethanolamines as full beta 3 agonists. Substitution of the ethanolamine nitrogen with a benzyl group bearing a para hydrogen bond acceptor promoted beta(3) selectivity. SAR elucidation established that highly selective beta(3) agonists were generated upon substitution of C(alpha) with either benzyl to form (R)-1,2-diarylethylamines or with aryl to generate 1,1-diarylmethylamines. This latter subset yielded a clinical candidate, BMS-194449 (35).(1)
A series of 4-hydroxy-3-methylsulfonanilido-1,2-diarylethylamines were prepared and evaluated for their human beta(3) adrenergic receptor agonist activity. SAR studies led to the identification of BMS-196085 (25), a potent beta(3) full agonist (K(i)=21 nM, 95% activation) with partial agonist (45%) activity at the beta(1) receptor. Based on its desirable in vitro and in vivo properties, BMS-196085 was chosen for clinical evaluation.
A series of 7,6- and 7,5-fused bicyclic thiazepinones and oxazepinones were generated and incorporated as conformationally restricted dipeptide surrogates in mercaptoacyl dipeptides. These compounds are potent inhibitors of angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) both in vitro and in vivo. Compound 1a, a 7,6-fused bicyclic thiazepinone, demonstrated excellent blood pressure lowering in a variety of animal models characterized by various levels of plasma renin activity and significantly potentiated urinary sodium, ANP, and cGMP excretion in a cynomolgus monkey assay. On the basis of its potency and duration of action, compound 1a (BMS-186716) was advanced into clinical development for the treatment of hypertension and congestive heart failure.
The depressor and renal responses to C-type natriuretic peptide (CNP) were determined in conscious cynomolgus monkeys treated with vehicle or inhibitors of neutral endopeptidase EC 3.4.24.11 (NEP) and angiotensin-converting enzyme (ACE). The NEP inhibitor SQ 28603 (100 mumol/kg intravenously, i.v.) significantly (p < 0.05) enhanced the depressor responses to 1 and 10 nmol/ kg i.v. CNP from -2 +/- 3 to -22 +/- 10 mm Hg and from -16 +/- 4 to -66 +/- 4 mm Hg, respectively. SQ 28603 also significantly increased the cyclic GMP responses to 1 and 10 nmol/kg CNP from 1.4 +/- 1.6 to 11.0 +/- 2.0 nmol/2 h and from 4.2 +/- 0.5 to 53.3 +/- 12.1 nmol/2 h, respectively. Furthermore, the NEP inhibitor significantly increased the natriuretic activity of 1 and 10 nmol/kg i.v. CNP from 235 +/- 99 to 760 +/- 60 microEq/2 h and from 399 +/- 208 to 1,036 +/- 79 microEq/2 h, respectively. A positive correlation between the cumulative natriuretic and cyclic GMP responses suggested a cyclic GMP-mediated mechanism. These data are consistent with the protection of CNP from degradation by renal NEP. Inhibition of ACE by 100 mumol/kg i.v. captopril did not significantly alter the depressor or renal activities of 1 nmol/kg of CNP, neither did it alter the potentiation of CNP activity by SQ 28603. The potentiation of the depressor, cyclic GMP, and natriuretic responses to CNP in nonhuman primates by SQ 28603 suggested that NEP is an important mechanism for in vivo inactivation of natriuretic peptides, including CNP.
In a previous study, the depressor activity of combined selective inhibitors of neutral endopeptidase EC 3.4.24.11 (NEP) and angiotensin-converting enzyme (ACE) depended on the level of ACE inhibition, whereas the renal responses were determined by NEP inhibition. Our study confirmed that a mixed NEP/ACE inhibitor BMS-182657 ([S-(R*,R*)]-2,3,4,5-tetrahydro-3-[(2-mercapto-1-oxo-3- phenylpropyl)amino]-2-oxo-1H-benzazepine-1-acetic acid) reduced mean arterial pressure (MAP) when renin release was reduced by a sodium load, suggesting that the depressor response did not require suppression of endogenous angiotensin II generation. Furthermore, a pressor dose of 30 ng/min of angiotensin II was required to block the depressor response to BMS-182657 in the presence or absence of exogenous human atrial natriuretic peptide (hANP 99-126). Thirty ng/min of angiotensin II also significantly enhanced the natriuresis induced by hANP 99-126 after BMS-182657 administration. In contrast, a nonpressor dose of angiotensin II (3 ng/min) reduced basal sodium excretion and the natriuretic responses to exogenous hANP 99-126 in the presence or absence of BMS-182657. The potentiation of the urinary ANP and cyclic guanosine monophosphate (cGMP) responses to hANP 99-126 by BMS-182657 was similar for all doses of angiotensin II; therefore angiotensin did not alter the effects of BMS-182657 on ANP metabolism or cGMP accumulation in the kidney. In summary, the renal responses to mixed metalloprotease inhibitors were apparently mediated by ANP potentiation and were modulated by angiotensin II. The depressor activity depended on ACE inhibition but was not mediated solely by reductions in endogenous angiotensin II levels.
The natriuretic and depressor responses to novel dual inhibitors of neutral endopeptidase (NEP) EC 3.4.24.11 and angiotensin-converting enzyme (ACE) were used to assess their activity in conscious cynomolgus monkeys. A survey of mercaptopropanoyl inhibitors revealed that compounds containing alanylproline or certain surrogates reduced blood pressure and increased sodium excretion, indicating a desirable profile of in vivo activity. Additional compound evaluation required specific in vivo assays for NEP and ACE inhibition. Accordingly, the potency of novel inhibitors against NEP and ACE were determined in conscious monkeys by the potentiation of the natriuretic activity of exogenous human atrial natriuretic peptide and inhibition of the pressor response to angiotensin I, respectively. This strategy led to the discovery that optimal in vivo activity was achieved when the mercaptopropanoyl group was replaced with mercaptoacetyl and the C-terminal alanylproline was replaced with conformationally constrained dipeptidomimetics. This work culminated in the identification of BMS-182657 as a prototypic dual NEP/ACE inhibitor with a highly desirable profile of in vivo pharmacology.
Simultaneous inhibition of neutral endopeptidase EC 3.4.24.11 (NEP) and angiotensin converting enzyme (ACE) by equimolar doses (100 mumol/kg i.v.) of SQ 28603 (N-[2-(mercaptomethyl)-1-oxo-3- phenylpropyl]-beta-alanine) and captopril increased sodium excretion by 888 +/- 377 microEq/3 hr and significantly lowered blood pressure by -6 +/- 2 mm Hg in conscious cynomolgus monkeys. This rate of sodium excretion was not significantly different from that elicited by 100 mumol/kg i.v. of SQ 28603 alone (1453 +/- 315 microEq/3 hr). In addition, the natriuretic response to captopril plus SQ 28603 was potentiated by infusion of 10 pmol/kg/min of human atrial natriuretic peptide (hANP 99-126) despite a reduction in renal perfusion pressure from 100 +/- 2 to 86 +/- 2 mm Hg. Lower doses (0.3 to 3 mumol/kg i.v.) of SQ 28603 that had no effect on blood pressure or renal function potentiated the natriuretic, urinary cyclic guanosine monophosphate and atrial natriuretic peptide responses without affecting the depressor activity of 0.3 nmol/kg i.v. of hANP 99-126. The potentiation of the natriuretic activity of 0.3 nmol/kg of hANP 99-126 by 1 or 3 mumol/kg of SQ 28603 was not significantly affected by the addition of equimolar doses of captopril. These results confirmed that the renal responses to the combined inhibitors resulted from NEP inhibition. In contrast, the depressor activity of the combined inhibitors was dependent on the level of ACE inhibition and was not significantly affected by either infusion of hANP 99-126 or prior sodium loading. Therefore, the vascular responses to combined NEP and ACE inhibitors did not necessarily depend upon increases in circulating atrial natriuretic peptide or reductions in angiotensin II levels. The unique profile of renal and vascular responses to combined NEP and ACE inhibition suggested that dual NEP/ACE inhibitors may be useful for the treatment of cardiovascular disorders.
1. Inhibitors of neutral endopeptidase (NEP) EC 3.4.24.11 were developed to regulate endogenous levels of the natriuretic and vasodilatory hormone atrial natriuretic peptide (ANP). The selective NEP inhibitor SQ 28603 enhanced the increases in plasma ANP and urinary excretion of ANP, cyclic GMP and sodium stimulated by infusion of human ANP in conscious monkeys. SQ 28603 also potentiated the renal and depressor responses to rat brain natriuretic peptide (BNP) in conscious spontaneously hypertensive rats (SHR) and human BNP in conscious monkeys. Therefore, selective NEP inhibitors protected both natriuretic peptides from degradation in vivo and enhanced their biological activities. 2. Selective NEP inhibitors lowered blood pressure in conscious DOCA/salt hypertensive rats and SHR with antihypertensive activity similar to that of exogenous ANP. Furthermore, simultaneous treatment with an angiotensin converting enzyme (ACE) inhibitor enhanced the depressor activity of the NEP inhibitor in SHR. 3. SQ 28603 stimulated urinary excretion of cyclic GMP and sodium in a dose-related manner in conscious dogs with tachycardia-induced heart failure. Addition of the ACE inhibitor captopril significantly reduced blood pressure and systemic vascular resistance while sustaining sodium excretion and increasing cardiac output, glomerular filtration rate and renal blood flow. Therefore, combined NEP and ACE inhibition produced a unique haemodynamic and renal profile in dogs with pacing-induced heart failure. 4. The novel dual metalloprotease inhibitor BMS-182657 potentiated the renal responses to exogenous ANP and suppressed the pressor response to angiotensin I in conscious monkeys, indicating in vivo inhibition of both NEP and ACE.(ABSTRACT TRUNCATED AT 250 WORDS)
The depressor, natriuretic and cyclic GMP responses to several species of brain natriuretic peptide (BNP) were compared to atrial natriuretic peptide (ANP) 99-126 in conscious spontaneously hypertensive rats (SHR) and in conscious cynomolgus monkeys treated with vehicle or the selective neutral endopeptidase (NEP 3.4.24.11) inhibitor N-[2-(mercaptomethyl)-1-oxo-3-phenylpropyl]-beta- alanine (SQ 28,603). In the conscious SHR, the natriuretic and cyclic GMP responses to 3 nmol/kg i.v. rat BNP-32 greater than rat ANP 99-126 greater than pig BNP-26 and were significantly potentiated by 100 mumol/kg i.v. SQ 28,603. Human BNP-32 was inactive in the SHR treated with either vehicle or SQ 28,603. In contrast, 1 nmol/kg i.v. of human BNP-32 stimulated renal and depressor responses in the conscious monkeys that were greater than or equal to those elicited by human ANP 99-126, whereas 3 nmol/kg i.v. rat BNP-32 reduced mean arterial pressure without affecting renal function. Furthermore, SQ 28,603 (100 mumol/kg, i.v.) significantly enhanced the cumulative losses of sodium and cyclic GMP stimulated by each of these peptides. In conclusion, the renal and depressor activities of BNP are highly species specific and are significantly potentiated by an inhibitor of NEP 3.4.24.11 in conscious SHR and monkeys. Therefore, protection of endogenous BNP may contribute importantly to the activity of NEP 3.4.24.11 inhibitors in cardiorenal disorders such as hypertension and congestive heart failure.
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A structurally novel pyrazolo[1,5-c]quinazoline, SQ 13,847, was demonstrated to be an orally active antiallergic agent. The compound inhibited immunoglobulin (Ig)E-mediated passive cutaneous anaphylaxis (PCA) and passive pulmonary anaphylaxis in the rat (ID50 = 2 to 4 mg/kg p.o.), but failed to affect IgG-mediated PCA in the rat, IgE-mediated PCA in the mouse or IgG1-mediated PCA in the guinea pig. The relative potencies of SQ 13,847 and its 2-carboxylic acid metabolite, SQ 12,903, upon oral vs. intravenous administration were consistent with a role of SQ 13,847 as an orally absorbed prodrug of SQ 12,903. In the rat, SQ 13,847 is not an antagonist of histamine in serotonin, in beta adrenergic agonist or a bronchodilator.
Changes in pulmonary function, as measured by airway conductance and dynamic compliance, in normal rats have been provoked by the administration of a rabbit antisera prepared against rat IgE myeloma protein. The response is specific in that neither anti-IgG nor normal rabbit serum induced pulmonary changes. Pre-treatment with disodium cromoglycate inhibits the bronchospasm in a dose related manner. In addition, drug protection can be demonstrated with as long 1 hr pre-dosing.