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
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
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
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.
