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A series of non-nucleoside adenosine kinase (AK) inhibitors is reported. These inhibitors originated from the modification of 5-(3-bromophenyl)-7-(6-morpholin-4-ylpyridin-3-yl)pyrido[2,3-d]pyrimidin-4-ylamine (ABT-702). The identification of a linker that would approximate the spatial arrangement found between the pyrimidine ring and the aryl group at C(7) in ABT-702 was a key element in this modification. A search of potential linkers led to the discovery of an acetylene moiety as a suitable scaffold. It was hypothesized that the aryl acetylenes, ABT-702, and adenosine bound to the active site of AK (closed form) in a similar manner with respect to the orientation of the heterocyclic base. Although potent acetylene analogs were discovered based on this assumption, an X-ray crystal structure of 5-(4-dimethylaminophenyl)-6-(6-morpholin-4-ylpyridin-3-ylethynyl)pyrimidin-4-ylamine (16a) revealed a binding orientation contrary to adenosine. In addition, this compound bound tightly to a unique open conformation of AK. The structure-activity relationships and unique ligand orientation and protein conformation are discussed.

The synthesis and structure-activity relationship of a series of 6,7-disubstituted 4-aminopyrido[2,3-d]pyrimidines as novel non-nucleoside adenosine kinase inhibitors is described. A variety of substituents, primarily aryl, at the C6 and C7 positions of the pyridopyrimidine core were found to yield analogues that are potent inhibitors of adenosine kinase. In contrast to the 5,7-disubstituted and 5,6,7-trisubstituted pyridopyrimidine series, these analogues exhibited only modest potency to inhibit AK in intact cells.

Adenosine kinase (AK) is the primary enzyme responsible for adenosine metabolism. Inhibition of AK effectively increases extracellular adenosine concentrations and represents an alternative approach to enhance the beneficial actions of adenosine as compared to direct-acting receptor agonists. Clitocine (3), isolated from the mushroom Clitocybe inversa, has been found to be a weak inhibitor of AK. We have prepared a number of analogues of clitocine in order to improve its potency and demonstrated that 5'-deoxy-5'-amino-clitocine (7) improved AK inhibitory potency by 50-fold.

A series of N-aryl cinnamides has been prepared and assayed for antagonism of the leukotriene B4 receptor. Several compounds in this series were found to be highly potent antagonists of the human neutrophil receptor, based on a whole cell binding assay, as well as a neutrophil aggregation assay. This series is unique among LTB4 antagonists, due to its high degree of rigidity.

Enantiomerically pure pyrrolidinones were synthesized as endothelin receptor antagonists. A [2+2] cycloaddition of an imine and an enantiomerically pure acid chloride gave two diastereomeric β-lactams which were separated and rearranged to give the enantiomerically pure pyrrolidinones which could be reduced to give the corresponding pyrrolidines.

As knowledge of the molecular biology of purinergic receptors continues to evolve, the identification of novel compounds that mimic or block the actions of the purine nucleoside and its nucleotide, ATP, at P1 and P2 receptor subtypes, respectively, has continued to be an area of active interest in the pharmaceutical industry. Adenosine A1 receptor selective agonists with reduced cardiovascular liabilities have been recently described, as have novel A3 receptor selective agonists; both classes of agents showing potential as anti-ischaemic agents in animal models. A number of potent and receptor subtype selective agonists for P2 receptors have also been developed that are being used to characterise the functional role of this receptor class in various mammalian tissues. On the antagonist front, selective A1 receptor antagonists are being targeted as cognition enhancers while selective A2a receptor antagonists have been developed with potential use in Parkinson's disease therapy. Despite the clinical failure...

Analogs of captopril and enalapril with a thiorphan-like substituent at the 4-position of the proline ring were synthesized and found to be dual inhibitors of angiotensin converting enzyme (ACE) and neutral endopeptidase 24.11 (NEP).

In this Letter we describe the optimization of an aminopurine lead (1) with modest potency and poor overall kinase selectivity which led to the identification of a series of potent, selective JNK inhibitors. Improvement in kinase selectivity was enabled by introduction of an aliphatic side chain at the C-2 position. CC-359 (2) was selected as a potential clinical candidate for diseases manifested by ischemia reperfusion injury.

Enantiomerically pure pyrrolidinones were synthesized as endothelin receptor antagonists. A [2+2] cycloaddition of an imine and an enantiomerically pure acid chloride gave two diastereomeric β-lactams which were separated and rearranged to give the enantiomerically pure pyrrolidinones which could be reduced to give the corresponding pyrrolidines.

A series of N-aryl cinnamides has been prepared and assayed for antagonism of the leukotriene B4 receptor. Several compounds in this series were found to be highly potent antagonists of the human neutrophil receptor, based on a whole cell binding assay, as well as a neutrophil aggregation assay. This series is unique among LTB4 antagonists, due to its high degree of rigidity.

Adenosine kinase (AK) is the primary enzyme responsible for adenosine metabolism. Inhibition of AK effectively increases extracellular adenosine concentrations and represents an alternative approach to enhance the beneficial actions of adenosine as compared to direct-acting receptor agonists. Clitocine (3), isolated from the mushroom Clitocybe inversa, has been found to be a weak inhibitor of AK. We have prepared a number of analogues of clitocine in order to improve its potency and demonstrated that 5'-deoxy-5'-amino-clitocine (7) improved AK inhibitory potency by 50-fold.

(3-Pyridinyl)alkanoic acids substituted at the 4-position with an (arylsulfonamido)alkyl group were synthesized and found to behave as platelet thromboxane receptor antagonists (TxRAs) and thromboxane synthase inhibitors (TxSIs). The compounds behaved as agonists at the vascular receptor for thromboxane A2.

A series of 8-[(arylsulfonyl)amino]octanoic acids substituted with a pyridinylalkyl group along the chain were synthesized and tested in vitro for their ability to both antagonize the binding of thromboxane A2 to its receptors and to inhibit the thromboxane synthase enzyme. This series of compounds were found to inhibit the U 46619-induced aggregation of human platelets and the U 46619-induced contraction of dog saphenous vein. The compounds also inhibited TxA2 biosynthesis in a human microsomal platelet preparation. The relative position of the pyridinylalkyl and arylsulfonamide groups had significant effects on the thromboxane receptor antagonist (TxRA) activity and thromboxane synthase inhibitor (TxSI) activity. Compounds with the pyridine ring at the 7- or 8-position of the octanoic acid side chain were weakly active as TxSI but behaved as potent TxRA at the platelet receptor for TxA2. However, these compounds were agonists at the vascular receptor. Substitution of the pyridinylalkyl group at the 2- or 3-position resulted in compounds with potent TxSI activity and weak TxRA activity. The activity profile of the compounds with the pyridinylalkyl substitution at the 4-, 5-, or 6-position was very desirable. Compound 22 with a pyridinylpropyl substituent at the 4-position was found to display extremely potent TxRA and TxSI properties.

The title compound (10a) and its analogs were synthesized and found to possess two activities, the inhibition of the biosynthesis of thromboxane A2 and antagonism of its receptors. The in vitro and in vivo profile of these compounds as thromboxane receptor antagonists (TxRAs) and thromboxane synthase inhibitors (TxSIs) is described. 10a and its analogs displayed very potent TxRA activity in human washed platelets (IC50 approximately 10(-7)-10(-9) M) and dog saphenous vein (pA2 approximately 9) and also potent TxSI activity (IC50 approximately 10(-9) M). The good bioavailability and the long duration of action of some of these compounds was demonstrated using ex vivo measurement of the TxRA activity upon oral administration to guinea pigs. Compounds 10a, 20, and 33 potently inhibited arachidonic acid induced bronchoconstriction in guinea pigs.

Adenosine kinase (AK) is an enzyme responsible for converting endogenous adenosine (ADO) to adenosine monophosphate (AMP) in an adenosine triphosphate- (ATP-) dependent manner. The structure of AK consists of two domains, the first a large alpha/beta Rossmann-like nucleotide binding domain that forms the ATP binding site, and a smaller mixed alpha/beta domain, which, in combination with the larger domain, forms the ADO binding site and the site of phosphoryl transfer. AK inhibitors have been under investigation as antinociceptive, antiinflammatory, and anticonvulsant as well as antiinfective agents. In this work, we report the structures of AK in complex with two classes of inhibitors: the first, ADO-like, and the second, a novel alkynylpyrimidine series. The two classes of structures, which contain structurally similar substituents, reveal distinct binding modes in which the AK structure accommodates the inhibitor classes by a 30 degrees rotation of the small domain relative to the large domain. This change in binding mode stabilizes an open and a closed intermediate structural state and provide structural insight into the transition required for catalysis. This results in a significant rearrangement of both the protein active site and the orientation of the alkynylpyrimidine ligand when compared to the observed orientation of nucleosidic inhibitors or substrates.

Three new approaches have been tested to modify existing pyridopyrimidine and alkynylpyrimidine classes of nonnucleoside adenosine kinase inhibitors 2 and 3. 4-Amino-substituted pteridines 8a–e were generally less active than corresponding 5- and 6-substituted pyridopyrimidines 2. Pyrazolopyrimidine 13c with IC50=7.5 nM was superior to its open chain alkynylpyrimidine analog 13g (IC50=22 nM) while pyrrolopyrimidines such as 17a were inactive.

Three new approaches have been tested to modify existing pyridopyrimidine and alkynylpyrimidine classes of nonnucleoside adenosine kinase inhibitors 2 and 3. 4-Amino-substituted pteridines 8a–e were generally less active than corresponding 5- and 6-substituted pyridopyrimidines 2. Pyrazolopyrimidine 13c with IC50=7.5 nM was superior to its open chain alkynylpyrimidine analog 13g (IC50=22 nM) while pyrrolopyrimidines such as 17a were inactive.

The synthesis and structure-activity relationship of a series of 5,6,7-trisubstituted 4-aminopyrido[2,3-d]pyrimidines as novel nonnucleoside adenosine kinase inhibitors is described. A variety of alkyl, aryl, and heteroaryl substituents were found to be tolerated at the C5, C6, and C7 positions of the pyridopyrimidine core. These studies have led to the identification of analogues that are potent inhibitors of adenosine kinase with in vivo analgesic activity.

Starting from a phenol screening hit (6), three series of benzopyranone selective estrogen receptor modulators (SERMs) have been designed, synthesized, and analyzed for both estrogen receptor alpha binding affinity and in vitro activity in two cell assays. The lead compound identified, SP500263 (13), was more potent than raloxifene and tamoxifen in a cell-based assay measuring inhibition of interleukin-6 release.

Publisher Summary This chapter presents an overview of different approaches leading to the discovery of dual angiotensin converting enzyme and neutral endopeptidase (ACE/NEP) inhibitors. ACE is a membrane bound glycoprotein, which plays a major role in the renin-angiotensin-aldosterone system by cleaving the C-terminal dipeptide portion (His-Leu) of angiotensin I (AI) to produce angiotensin II (AII) which is a potent vasoconstrictor. On the other hand, neutral endopeptidase is a 90 kDa membrane bound glycoprotein, which hydrolyzes peptides at the amino group of hydrophobic residues. Design of novel compounds which inhibits both ACE and NEP has been facilitated by examination of the structural features of the selective ACE and selective NEP inhibitors. ACE and NEP are both zinc metalloproteases with one zinc atom in their active site. The thiol group seems to be a good functional group to incorporate in the design of dual ACE/NEP inhibitors as it binds to zinc ion with high affinity.

Publisher Summary This chapter discusses the identification of specific ligands, agonists, antagonists, and allosteric modulators to define the physiological/pharmacological function of P 2 purinoceptors. Purinoceptors have been originally divided into P 1 (ADO) and P 2 (adenosine triphosphate; ATP) subclasses. Pharmacological evaluation led to the classification of P 2X and P 2Y classes with the addition of P 2T and P 2Z receptors. Adenosine triphosphate (ATP) is an unusual candidate for a neurotransmitter, this role being conceptually viewed as an unorthodox use of cellular energy stores. As well as interacting with the members of the P 2 receptor family, ATP can be broken down via synaptic ectonucleotidase action to form adenosine (ADO), a neuromodulator in its own right. ATP can also modulate ADO interactions at the A 1 receptor. P 2 receptor nomenclature is currently in a state of considerable flux, evolving from a pharmacological basis to the state that relates receptor cloning to function. From a drug discovery perspective, it is a major step from the cloning and expression of the members of a new receptor family to defining their function. All known agonist ligands for the P 2 receptor family are variations on the purine nucleotide pharmacophore. The identification of novel pharmacophores selective for P 2 receptors that can be used to unambiguously characterize the various members of the receptor superfamily is critical to advancing the field. The P 2 receptor legands are potential of different therapeutic use. ATP is an effective and long-lasting inhibitor of human tumor cell growth. Again, ATP can be used as an adjunct to inhalation anesthetics. ATP and uridine triphosphate (UTP) have been evaluated as treatments for cystic fibrosis. P 2 receptor mechanisms may also be involved in cell adhesion. Thus, P 2 purinoceptors remains a key element in the discovery of new therapeutic agents.

The enantiomers of 8-[[(4-chlorophenyl)sulfonyl]amino]-4-(3-pyridinylpropyl)octanoic acid (1) and its pyridinyl ether analog (2) were synthesized using the highly diastereoselective method of alkylation of acyloxazolidinone. These enantiomerically pure compounds were compared with the corresponding racemic compounds 1 and 2 for their in vitro activity. Compounds 1, 1R, and 1S and 2,2S, and 2R were equipotent as thromboxane receptor antagonists (TxRAs) and thromboxane synthase inhibitors (TxSIs) (IC50 = 2-30 nM). Upon oral administration to guinea pigs, the enantiomers inhibited the ex vivo U 46619-induced platelet aggregation with potency similar to that of the corresponding racemic compound. This indicates that the enantiomers have pharmacologic profile and bioavailability similar to that of the corresponding racemic compound.

The design, synthesis, and in vitro pharmacology of a new class of compounds exerting both thromboxane receptor antagonist and thromboxane synthase inhibitory activities is described. [(3-Pyridinyl)bicycloheptyl] alkanoic acid 9 and its analogues, designed with the help of molecular modeling, were synthesized and found to be inhibitors of thromboxane A2 (TxA2) biosynthesis in a human platelet microsomal preparation. The compounds were also found to antagonize both platelet and vascular TxA2 receptors. The compounds inhibited the U 46619 induced aggregation of human washed platelets and platelet-rich plasma and the U 46619 induced contraction of the dog saphenous vein.

Synthese du butyl-3 methyl-4 dioxa-2,6bicyclo [3.1.1] heptane par cyclodeshydratation du butyl-6 dibromo-3,3 methyl-5 perhydro pyrannediol-2,4(A) suivie de reduction par SnBu 3 H(A) est prepare a partir de methyl-2 heptene-2al

In 1975, Hamberg et al. reported evidence for the existence of an unstable platelet-aggregating factor which they named thromboxane A2 (TXA2) and for which they proposed a novel bicyclic oxetane structure (1, below) based on the short half-life of the factor (t1/2 (37 degrees C) = 32 s at pH 7.4) and the isolation of degradation products related to thromboxane (TXB2) (2, below). As natural TXA2 has not yet been isolated and characterized as a pure compound, we have synthesized the proposed structure (1) from TXB2 and compared its biological properties with those of authentic, biologically generated material. Here we present evidence that synthetic material having structure (1) is indistinguishable from platelet-derived TXA2 in various biological assays and that the proposed structure (1) for TXA2 is correct.