ABSTRACT
A new MMP12 inhibitor series has been identified containing a thiophene moiety. Different approaches have been considered to replace this potential toxicophore. α-Fluorothiophene derivatives were the most interesting compounds. Their synthesis is presented.
Subject(s)
Matrix Metalloproteinase Inhibitors , Protease Inhibitors/chemistry , Thiophenes/chemistry , Matrix Metalloproteinase 12/metabolism , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , Structure-Activity Relationship , Thiophenes/chemical synthesis , Thiophenes/pharmacologyABSTRACT
The synthesis and SAR studies of a series of structurally novel small molecule inhibitors of PDE7 are discussed. The best compounds from the series displayed low nanomolar inhibitory activity and are selective versus PDE4.
Subject(s)
3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors , Isoenzymes/antagonists & inhibitors , Phosphodiesterase Inhibitors/chemical synthesis , Phosphodiesterase Inhibitors/pharmacology , Thiadiazoles/chemical synthesis , Thiadiazoles/pharmacology , 3',5'-Cyclic-AMP Phosphodiesterases/metabolism , Cell Line , Cyclic Nucleotide Phosphodiesterases, Type 4 , Cyclic Nucleotide Phosphodiesterases, Type 7 , Humans , Isoenzymes/metabolism , Phosphodiesterase Inhibitors/chemistry , Structure-Activity Relationship , Thiadiazoles/chemistryABSTRACT
The synthesis and optimization of pharmacokinetic parameters of structurally novel small PDE7 inhibitors is discussed.
Subject(s)
3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors , Isoenzymes/antagonists & inhibitors , Phosphodiesterase Inhibitors/pharmacokinetics , Thiadiazoles/pharmacokinetics , 3',5'-Cyclic-AMP Phosphodiesterases/metabolism , Administration, Oral , Animals , Biological Availability , Cyclic Nucleotide Phosphodiesterases, Type 7 , Isoenzymes/metabolism , Phosphodiesterase Inhibitors/chemical synthesis , Phosphodiesterase Inhibitors/chemistry , Rats , Stereoisomerism , Structure-Activity Relationship , Thiadiazoles/chemical synthesis , Thiadiazoles/chemistryABSTRACT
The synthesis and SAR studies of spiroquinazolinones as novel PDE7 inhibitors are discussed. The best compounds from the series displayed nanomolar inhibitory affinity and were selective versus other PDE isoenzymes.
Subject(s)
3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors , Isoenzymes/antagonists & inhibitors , Phosphodiesterase Inhibitors/chemical synthesis , Quinazolines/chemical synthesis , Spiro Compounds/chemical synthesis , 3',5'-Cyclic-AMP Phosphodiesterases/metabolism , Cell Line , Cyclic Nucleotide Phosphodiesterases, Type 7 , Drug Evaluation, Preclinical , Humans , Isoenzymes/metabolism , Phosphodiesterase Inhibitors/chemistry , Phosphodiesterase Inhibitors/pharmacology , Quinazolines/chemistry , Quinazolines/pharmacology , Solubility , Spiro Compounds/chemistry , Spiro Compounds/pharmacology , Structure-Activity RelationshipSubject(s)
3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors , Cycloheptanes/chemistry , Phosphodiesterase Inhibitors/chemistry , 3',5'-Cyclic-AMP Phosphodiesterases/metabolism , Azulenes , Cyclic Nucleotide Phosphodiesterases, Type 4 , Cycloheptanes/pharmacology , Phosphodiesterase Inhibitors/pharmacologyABSTRACT
The 1-(2-nitrophenyl)thiosemicarbazide (TSC) derivative, (S)-1-[4-(4-benzhydrylthiosemicarbazido)-3-nitrobenzenesulfonyl]pyrrolidine-2-carboxylic acid [2-[(2-dimethylaminoethyl)methylamino]ethyl]amide (bradyzide; (S)-4), was recently disclosed as a novel, potent, orally active nonpeptide bradykinin (BK) B2 receptor antagonist. The compound inhibited the specific binding of [3H]BK to NG108-15 cell membrane preparations (rodent neuroblastoma-glioma) expressing B2 receptors with a K(i) of 0.5 +/- 0.2 nM. Compound (S)-4 also demonstrated oral efficacy against Freund's complete adjuvant (FCA)-induced mechanical hyperalgesia in rats with an ED50 value of 0.84 micromol/kg. After we optimized the terminal binding determinants projecting from the TSC framework, we found that it was possible to replace the potentially toxicophoric nitro and divalent sulfur moieties with only a 15-fold loss in binding affinity ((S)-14a). However, bradyzide and its congeners were found to have much lower affinities for cloned human B2 receptors, expressed in Cos-7 cells. The hitherto synthesized TSC series was screened against the human B2 receptor, and the dibenzosuberane (DBS) pharmacophore emerged as the key structural requirement for potency. Incorporation of this group resulted in a series of derivatives ((S)-14d,e and 19b-d) with K(i) ranges of 10.7-176 nM in NG108-15 cells (expressing the rodent B2 receptor) and 0.79-253 nM in Cos-7 cells (expressing the human B2 receptor). There was no evidence of agonist activity with any of the nonpeptides in any of the cell lines tested. In vivo, oral administration of compound 19c reversed FCA-induced and turpentine-induced mechanical hyperalgesia in rodents with ED50 values of 0.027 and 0.32 micromol/kg, respectively. The selectivity profiles of compounds (S)-14f and (S)-14g were also assessed to determine the conformational and/or steric preferences of the double-ring arrangement. The affinity of (S)-14 g for the human B2 receptor suggested that it may be a hydrophobic interaction with the ethane bridge of the DBS moiety that accounts for the increased potency of compounds (S)-14d,e and 19b,c at this receptor, by favoring a binding mode inaccessible to the unsubstituted diphenylmethyl derivative, (S)-4.