ABSTRACT
Truncation of the original piperidino-2(S)-methyl piperazine lead structure 2, from a family of muscarinic antagonists, gave compound 8 which has improved selectivity for the HIV-1 co-receptor CCR5 over muscarinic receptors. Further optimization for pharmacokinetic properties afforded Sch-350634 (1), a prototypical piperazine-based CCR5 antagonist, which is a potent inhibitor of HIV-1 entry and replication in PBMCs. The title compound (1) has excellent oral bioavailability in rat, dog, and monkey.
Subject(s)
Anti-HIV Agents/chemical synthesis , CCR5 Receptor Antagonists , Cyclic N-Oxides/chemical synthesis , Piperazines/chemical synthesis , Administration, Oral , Animals , Anti-HIV Agents/chemistry , Anti-HIV Agents/pharmacokinetics , Anti-HIV Agents/pharmacology , Biological Availability , Cell Line , Cyclic N-Oxides/chemistry , Cyclic N-Oxides/pharmacokinetics , Cyclic N-Oxides/pharmacology , Dogs , HIV-1/drug effects , In Vitro Techniques , Leukocytes, Mononuclear/virology , Macaca fascicularis , Piperazines/chemistry , Piperazines/pharmacokinetics , Piperazines/pharmacology , Rats , Structure-Activity RelationshipABSTRACT
New blood vessel formation is essential for tumor growth and metastatic spread. Integrins alpha(v)beta3 and alpha(v)beta5 are arginine-glycine-aspartic acid-dependent adhesion receptors that play a critical role in angiogenesis. Hence, selective dual alpha(v)beta3 and alpha(v)beta5 antagonists may represent a novel class of angiogenesis and tumor-growth inhibitors. Here, an arginine-glycine-aspartic acid-based peptidomimetic library was screened to identify alpha(v)beta3 antagonists. Selected compounds were then modified to generate potent and selective dual inhibitors of alpha(v)beta3 and alpha(v)beta5 receptors. One of these compounds, SCH 221153, inhibited the binding of echistatin to alpha(v)beta3 (IC50 = 3.2 nM) and alpha(v)beta5 (IC50 = 1.7 nM) with similar potency. Its IC50 values for related alpha(IIb)beta3 and alpha5beta1 receptors were 1294 nM and 421 nM, respectively, indicating that SCH 221153 is highly selective for alpha(v)beta3 and alpha(v)beta5 receptors. In cell-based assays, SCH 221153 inhibited the binding of echistatin to alpha(v)beta3- and alpha(v)beta5-expressing 293 cells and blocked the adhesion of endothelial cells to immobilized vitronectin and fibroblast growth factor 2 (FGF2). SCH 221153, but not the inactive analogue SCH 216687, was effective in inhibiting FGF2 and vascular endothelial growth factor-induced endothelial cell proliferation in vitro with an IC50 equal to 3-10 microM. Angiogenesis induced by FGF2 in the chick chorioallantoic membrane assay was also inhibited by SCH 221153. Finally, SCH 221153 exerted a significant inhibition on tumor growth induced by intradermal or s.c. injection of human melanoma LOX cells in severe combined immunodeficient mice.
Subject(s)
Angiogenesis Inhibitors/pharmacology , Antineoplastic Agents/pharmacology , Integrins/antagonists & inhibitors , Neovascularization, Pathologic/drug therapy , Receptors, Vitronectin/antagonists & inhibitors , Allantois/blood supply , Animals , Cell Adhesion/drug effects , Cell Division/drug effects , Chick Embryo , Chorion/blood supply , Endothelial Growth Factors/antagonists & inhibitors , Endothelial Growth Factors/pharmacology , Endothelium, Vascular/cytology , Endothelium, Vascular/drug effects , Female , Fibroblast Growth Factor 2/antagonists & inhibitors , Fibroblast Growth Factor 2/metabolism , Fibroblast Growth Factor 2/pharmacology , Growth Inhibitors/pharmacology , Humans , Intercellular Signaling Peptides and Proteins , Lymphokines/antagonists & inhibitors , Lymphokines/pharmacology , Melanoma/blood supply , Melanoma/drug therapy , Melanoma/pathology , Mice , Mice, SCID , Molecular Mimicry , Neovascularization, Physiologic/drug effects , Oligopeptides/metabolism , Peptides/metabolism , Vascular Endothelial Growth Factor A , Vascular Endothelial Growth Factors , Vitronectin/metabolism , Xenograft Model Antitumor AssaysABSTRACT
A set of biphenyl aminoacid building blocks has been synthesized. These were used to construct partially-peptidic combinatorial libraries as equimolar multi-component samples. Activity of members of this library as vitronectin receptor antagonists is described, together with SAR studies of the most active members. These studies illustrate several important features of combinatorial libraries.
Subject(s)
Biphenyl Compounds/chemical synthesis , Databases as Topic , Receptors, Vitronectin/metabolism , Biphenyl Compounds/chemistry , Biphenyl Compounds/pharmacokinetics , Biphenyl Compounds/pharmacology , Drug Design , Isomerism , Kinetics , Molecular Conformation , Molecular Structure , Receptors, Vitronectin/drug effects , Structure-Activity RelationshipABSTRACT
Tetracyclic guanines have been shown to be potent and selective inhibitors of the cGMP-hydrolyzing enzymes PDE1 and PDE5. In general, these compounds are inactive or only weakly active as inhibitors of PDE3, which is a major isozyme involved in cAMP hydrolysis. Structure-activity relationships are developed at N-1, C-2, N-3, and N-5 on the core nucleus. Compound 31, with an IC50 of 70 pM, is the most potent inhibitor of PDE1, while 50, with an IC50 of 4 nM, is the most potent inhibitor of PDE5. Compounds 20, 22, 30, and 50 are potent dual inhibitors with IC50 values below 30 nM for both PDE1 and PDE5. Compounds 12, 20, and 28 reduced blood pressure by more than 45 mmHg when administered orally at 10 mg/kg to the spontaneously hypertensive rat (SHR).
Subject(s)
3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors , 3',5'-Cyclic-GMP Phosphodiesterases/antagonists & inhibitors , Antihypertensive Agents/chemical synthesis , Blood Pressure/drug effects , Guanine/analogs & derivatives , Guanine/chemical synthesis , Phosphodiesterase Inhibitors/chemical synthesis , Phosphoric Diester Hydrolases , Pyrroles , Administration, Oral , Animals , Antihypertensive Agents/chemistry , Antihypertensive Agents/pharmacology , Cyclic Nucleotide Phosphodiesterases, Type 1 , Cyclic Nucleotide Phosphodiesterases, Type 5 , Guanine/chemistry , Guanine/pharmacology , Indicators and Reagents , Isoenzymes/antagonists & inhibitors , Kinetics , Magnetic Resonance Spectroscopy , Molecular Structure , Phosphodiesterase Inhibitors/chemistry , Phosphodiesterase Inhibitors/pharmacology , Rats , Rats, Inbred SHR , Structure-Activity RelationshipABSTRACT
A broad series of N-(3-mercaptoacyl) amino acid derivatives was evaluated for their ability to inhibit atriopeptidase (neutral endopeptidase, EC 3.4.24.11) in vitro and in vivo. Structural parameters studied were (i) the substituent on the 2-position of the 3-mercaptopropionyl moiety, (ii) the amino acid component, (iii) the S-terminal derivative, and (iv) the C-terminal derivative. Optimum activity was observed for derivatives of methionine and S-alkylcysteines. N-[3-Mercapto-2(S)-[(2-methylphenyl)methyl]-1-oxopropyl]-L-methionine was identified as a highly effective inhibitor of atriopeptidase meriting evaluation as a potential cardiovascular therapeutic agent.
Subject(s)
Amino Acids/pharmacology , Antihypertensive Agents/pharmacology , Cysteine/analogs & derivatives , Methionine/chemistry , Neprilysin/antagonists & inhibitors , Amino Acid Sequence , Amino Acids/chemistry , Animals , Atrial Natriuretic Factor/pharmacology , Cholinesterase Inhibitors/pharmacology , Male , Molecular Sequence Data , Rats , Rats, Inbred SHR , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
Neutral metalloendopeptidase (NEP) inhibitors delay atrial natriuretic factor (ANF) catabolism and potentiate biological responses to ANF. We describe biochemical and pharmacological profiles of a novel NEP inhibitor, SCH 42354 (N-[2(S)-(mercaptomethyl)-3-(2-methylphenyl)-4-oxopropyl]-L-methionine and its orally active ethylester prodrug, SCH 42495. SCH 42354 selectively inhibited hydrolysis of leu-enkephalin and ANF (IC50 of 8.3 and 10.0 nmol/L, respectively) in vitro. Plasma levels of exogenous ANF were augmented and ANF clearance from plasma was delayed by oral SCH 42495 (3 to 30 mg/kg) in normotensive rats. Plasma ANF levels in volume expanded rats were higher in SCH 42495-treated rats. Diuretic and natriuretic effects of ANF were increased in rats treated with SCH 42495. Oral doses of 1, 3, or 10 mg/kg of SCH 42495 produced significant reductions in blood pressure in DOCA-Na hypertensive rats of 22 +/- 6, 43 +/- 7, and 62 +/- 12 mm Hg, respectively, which were not associated with increases in heart rate. These doses did not alter urine flow, salt excretion, or plasma ANF. SCH 42495 produced significant elevation of urinary excretion of ANF and cGMP. In Dahl-S hypertensive rats, SCH 42495 (1 to 10 mg/kg orally) produced falls in blood pressure of a magnitude similar to that observed in DOCA-Na hypertensive rats. Significant hypotensive activity was observed 18 h after a single 10 mg/kg oral dose in Dahl-S hypertensive rats. In DOCA-Na hypertensive rats, a single dose of SCH 42495 significantly decreased cardiac output and did not lower systemic vascular resistance, a profile similar to that of ANF. The hypotensive response to SCH 42495 was not ascribable to ACE inhibition. Pithed rat preparations revealed no interaction of the drug with autonomic cardiovascular function. The antihypertensive effect of SCH 42495 likely results from potentiation of endogenous ANF via NEP inhibition.
Subject(s)
Atrial Natriuretic Factor/pharmacology , Hemodynamics/drug effects , Metalloendopeptidases/antagonists & inhibitors , Animals , Antihypertensive Agents/pharmacology , Autonomic Nervous System/drug effects , Bradykinin/antagonists & inhibitors , Desoxycorticosterone , Drug Synergism , Hypertension/chemically induced , Hypertension/genetics , Kidney/drug effects , Male , Methionine/analogs & derivatives , Methionine/pharmacology , Rats , Rats, Inbred SHR , Rats, Inbred Strains , Rats, Mutant Strains , Sodium ChlorideABSTRACT
The synthesis of spirapril (5), spiraprilat (25), their RSS stereoisomers, and their glycyl (18b) and lysyl (36, 37) analogues is described. These compounds were evaluated in vivo for inhibition of angiotensin converting enzyme (ACE), and selected compounds were evaluated for in vitro ACE inhibition (spirapril ID50 16 micrograms/kg; spiraprilat IC50 0.8 nM, ID50 8 micrograms/kg). In anesthetized rats, iv, esters 5 and 36 are more potent than enalapril, and diacids 25 and 37 are more potent than enalaprilat in vitro. In the conscious rats, orally, 5 and enalapril (2) showed potent and sustained activity at doses of 0.03-1 and 0.1-1 mg/kg, respectively. From this work, spirapril was selected for clinical evaluation as an antihypertensive agent.
Subject(s)
Angiotensin-Converting Enzyme Inhibitors/chemical synthesis , Enalapril/analogs & derivatives , Phenylbutyrates/pharmacology , Spiro Compounds/pharmacology , Animals , Blood Pressure/drug effects , Chemical Phenomena , Chemistry , Dogs , Enalapril/pharmacology , Male , Rats , Rats, Inbred StrainsSubject(s)
Atrial Natriuretic Factor/pharmacology , Dipeptides/pharmacology , Hypertension/drug therapy , Neprilysin/antagonists & inhibitors , Alkylation , Animals , Atrial Natriuretic Factor/blood , Atrial Natriuretic Factor/therapeutic use , Blood Pressure/drug effects , Chemical Phenomena , Chemistry , Dipeptides/chemical synthesis , Dipeptides/therapeutic use , Drug Synergism , Half-Life , Kidney/enzymology , Neprilysin/metabolism , Rabbits , RatsABSTRACT
The synthesis of a series of N-(mercaptoacyl)-4-substituted-(S)-prolines (2 and 3) is described. These compounds were evaluated in vitro for inhibition of angiotensin-converting enzyme (ACE), and selected compounds were evaluated in vivo for ACE inhibition. The most potent compounds in vitro are 108, 109, 111, 114, and 116, having relative potencies of 1.0, 1.0, 1.3, 1.1, and 2.6 as compared to the potency of captopril. The most potent compounds in vivo intravenously are 108, 111, 114, 116, 117, and 97.