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Previous work investigating tricyclic pyrrolopyrazines as kinase cores led to the discovery that 1-cyclohexyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (12) had Jak inhibitory activity. Herein we describe our initial efforts to develop orally bioavailable analogs of 12 with improved selectivity of Jak1 over Jak2.

The ability to restrict low molecular weight compounds to the gastrointestinal (GI) tract may enable an enhanced therapeutic index for molecular targets known to be associated with systemic toxicity. Using a triazolopyrazine CSF1R inhibitor scaffold, a broad range of prodrugs were synthesized and evaluated for enhanced delivery to the colon in mice. Subsequently, the preferred cyclodextrin prodrug moiety was appended to a number of CSF1R inhibitory active parent molecules, enabling GI-restricted delivery. Evaluation of a cyclodextrin prodrug in a dextran sodium sulfate (DSS)-induced mouse colitis model resulted in enhanced GI tissue levels of active parent. At a dose where no significant depletion of systemic monocytes were detected, the degree of pharmacodynamic effect-measured as reduction in macrophages in the colon-was inferior to that observed with a systemically available positive control. This suggests that a suitable therapeutic index cannot be achieved with CSF1R inhibition by using GI-restricted delivery in mice. However, these efforts provide a comprehensive frame-work in which to pursue additional gut-restricted delivery strategies for future GI targets.

We report the SAR around a series of 2,4-diaminopyrimidine-5-carboxamide inhibitors of Sky kinase. 2-Aminophenethyl analogs demonstrate excellent potency but moderate kinase selectivity, while 2-aminobenzyl analogs that fill the Ala571 subpocket exhibit good inhibition activity and excellent kinase selectivity.

Mining of an in-house collection of angiotensin II type 1 receptor antagonists to identify compounds with activity at the peroxisome proliferator-activated receptor-γ (PPARγ) revealed a new series of imidazo[4,5-b]pyridines 2 possessing activity at these two receptors. Early availability of the crystal structure of the lead compound 2a bound to the ligand binding domain of human PPARγ confirmed the mode of interaction of this scaffold to the nuclear receptor and assisted in the optimization of PPARγ activity. Among the new compounds, (S)-3-(5-(2-(1H-tetrazol-5-yl)phenyl)-2,3-dihydro-1H-inden-1-yl)-2-ethyl-5-isobutyl-7-methyl-3H-imidazo[4,5-b]pyridine (2l) was identified as a potent angiotensin II type I receptor blocker (IC(50) = 1.6 nM) with partial PPARγ agonism (EC(50) = 212 nM, 31% max) and oral bioavailability in rat. The dual pharmacology of 2l was demonstrated in animal models of hypertension (SHR) and insulin resistance (ZDF rat). In the SHR, 2l was highly efficacious in lowering blood pressure, while robust lowering of glucose and triglycerides was observed in the male ZDF rat.

We have optimized the Pd-catalyzed intramolecular α-arylation of 2-(2-halo-benzyl)-cyclohexanones and found that the use of 2-(dicyclohexylphosphino)-2′,4′,6′-tri-i-propyl-1,1′-biphenyl (X-Phos) as an added ligand led to a reproducible, efficient, and scalable synthesis of tricycle-[7.3.1.02,7]-trideca-2,4,6-trien-13-ones.

IntroductionCheminformatics can be broadly described as any attempttousechemicalinformationtoinfertherelationshipsbetweenor attributes of chemical structures. From a drug discoveryperspective, cheminformatic principles can be applied fromthe earliest stages of lead discovery (e.g., chemical similarityand library design) to lead optimization (e.g., QSAR studies)through to preclinical and clinical development (e.g., predic-tive toxicology). The popularity of cheminformatics and itsuse in academia and the pharmaceutical industry can beappreciated from the fact that at least five scientific journalsexist almost exclusively dedicated to the field (The Journal ofCheminformatics, The Journal of Chemical Information andModeling, The Journal of Computer-Aided Molecular Design,Molecular Bioinformatics,andQSAR and CombinatorialScience), and more than 15000 scientific journal articles havebeen published during just the last 5 years that describecheminformatic research. This intense interest in cheminfor-matics stems from the promise that, if underlying relation-ships between a given chemical structure and a host ofbiological end points exist and can be elucidated, drug dis-covery timelines can be significantly reduced. Given thepressure on the pharmaceutical industry to increase produc-tivity while decreasing costs, prior knowledge of which mole-cules have the highest probability of success (or at leastknowing which molecules are likely to fail) is worthy ofvigorous pursuit.Over the past decade there have been several significantadvancements in our understanding and application of che-minformatic principles. Approaches to measuring and com-paring chemical information have become both moresophisticated and accessible. For example, two of the mostpowerfulchemicalsimilaritymeasures(two-dimensional(2D)extended connectivity fingerprints and three-dimensional(3D) shape and electrostatic overlays) are available in user-friendly software packages from Scitegic (Accelrys) andOpeneye Scientific Software. Multiple methods for under-standing and predictingbioactivity have proven their robust-ness,includingpartialleast-squares(PLS),geneticalgorithms,Bayesian analyses, and Random Forest analyses. Our under-standing of molecular features or properties associated withcertain pharmacological end points has also dramaticallyincreased. For example, it has been widely recognized thatcertain structural features can be associated with toxicity,while other molecular properties (such as ClogP, molecularweight, and polar surface area) can be associated with oralbioavailability

Aiming to improve upon previously disclosed Factor Xa inhibitors, a series of 4,4-disubstituted pyrrolidine-1,2-dicarboxamides were explored with the intent of increasing the projected human half-life versus 5 (projected human t1/2 = 6 h). A stereospecific route to compounds containing a 4-aryl-4-hydroxypyrrolidine scaffold was developed, resulting in several compounds that demonstrated an increase in the half-life as well as an increase in the in vitro potency compared to 5. Reported herein is the discovery of 26, containing a (2R,4S)-4-hydroxy-4-(2,4-difluorophenyl)-pyrrolidine scaffold, which is a selective, orally bioavailable, efficacious Factor Xa inhibitor that appears suitable for a once-daily dosing (projected human t1/2 = 23 h).

Compound I (4,5-dihydropyrazole-1,5-dicarboxylic acid-1-[(4-chlorophenyl)-amide] 5-[(2-oxo-2 H-[1,3']bipyridinyl-6'-yl)-amide] was found to undergo metabolic activation in rat liver microsomes in the presence of NADPH. A reactive intermediate, postulated to be p-chlorophenyl isocyanate (CPIC), was trapped by GSH in vitro and characterized by liquid chromatography tandem mass spectrometry (LC/MS/MS). Subsequently, the structure of the GSH conjugate was confirmed by a comparison with a synthetic standard. The GSH conjugate was also found in the bile of rats that received an oral dose (10 mg/kg) of compound I. Further analyses of rat bile and urine using online electrochemical derivatization coupled to LC/MS demonstrated the presence of p-chlorophenyl aniline (CPA), a hydrolytic product of the intermediate isocyanate. This provided further evidence for the potential existence of CPIC. Approximately 7% of the dose was accounted by the products of CPIC, which included the GSH conjugate and CPA excreted in bile and urine. Multiple rat cytochrome P450 enzymes, including P450 1A, P450 2C, and P450 3A, appeared to be responsible for the activation of compound I to CPIC. The activation kinetics of compound I to CPIC in male rat liver microsomes exhibited a biphasic profile, indicative of at least two contributing P450 enzymes. One enzyme showed a small value of K m at 42 microM and a low V max of 66 pmol min (-1) mg (-1), while the other exhibited a large value of K m at 148 microM and a high V max of 1200 pmol min (-1) mg (-1). The formation of a putative CPIC intermediate, a carbamoylating species known to be capable of covalent binding to macromolecules, suggests a potential liability associated with the compound, particularly the dihydropyrazole-1-carboxylic acid-(4-chlorophenyl amide) scaffold, which appears to be responsible for the generation of CPIC. The mechanism of bioactivation to the putative CPIC is postulated to involve an initial P450-mediated hydroxylation of the pyrazoline at the 3 position followed by subsequent decomposition to CPIC. This mechanistic insight into the bioactivation allowed for the development of a rational structural modification strategy to mitigate or minimize the reactive metabolite formation. One of the approaches included the introduction of a metabolically stable substituent with electron-donating character at the 3 position of pyrazoline to block CPIC formation.

We report the design and synthesis of a series of 6-(2,4-diaminopyrimidinyl)-1,4-benzoxazin-3-ones as orally bioavailable small molecule inhibitors of renin. Compounds with a 2-methyl-2-aryl substitution pattern exhibit potent renin inhibition and good permeability, solubility, and metabolic stability. Oral bioavailability was found to be dependent on metabolic clearance and cellular permeability, and was optimized through modulation of the sidechain that binds in the S3sp subsite.

Herein, we report the discovery of novel, proline-based factor Xa inhibitors containing a neutral P1 chlorophenyl pharmacophore. Through the additional incorporation of 1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one 22, as a P4 pharmacophore, we discovered compound 7 (PD 0348292). This compound is a selective, orally bioavailable, efficacious FXa inhibitor that is currently in phase II clinical trials for the treatment and prevention of thrombotic disorders.

A novel series of pyrrolidine-1,2-dicarboxamides was discovered as factor Xa inhibitors using structure-based drug design. This series consisted of a neutral 4-chlorophenylurea P1, a biphenylsulfonamide P4 and a D-proline scaffold (1, IC(50) = 18 nM). Optimization of the initial hit resulted in an orally bioavailable, subnanomolar inhibitor of factor Xa (13, IC(50) = 0.38 nM), which was shown to be efficacious in a canine electrolytic model of thrombosis with minimal bleeding.

A robust method has been developed to couple a wide variety of pyridin-2-ones and aryl halides. This C–N bond forming reaction makes use of catalytic copper(I) iodide and the ligand 8-hydroxyquinoline. These conditions tolerate a wide degree of functionality on both the aryl halide and pyridin-2-one reactants and have resulted in numerous examples being synthesized.

Factor Xa is a serine protease that has a critical role in the blood coagulation cascade by ultimately regulating the production of thrombin. There is now ample evidence for the role of Factor Xa inhibitors as anticoagulants and they represent potential new therapeutic agents for the treatment and prevention of arterial and venous thrombosis. During the past five years, research in the field of Factor Xa inhibitors has been marked with enormous efforts to identify highly potent, selective and orally-active agents. This research has led to the discovery of a number of clinical candidates that are currently progressing at different stages of drug development. This review examines the patent and scientific literature during the period 2000 – 2005.

The activated Factor VII/tissue factor complex (FVIIa/TF) plays a key role in the formation of blood clots. Inhibition of this complex may lead to new antithrombotic drugs. An X-ray crystal structure of a fluoropyridine-based FVIIa/TF inhibitor bound in the active site of the enzyme complex suggested that incorporation of substitution at the 5-position of the hydroxybenzoic acid side chain could lead to the formation of more potent inhibitors through interactions with the S1'/S2' pocket.

Inhibition of renin enzymatic activity by a series of ketopiperazine-based compounds containing a C6 benzyloxymethyl substituent correlated with a +(pi+sigma) effect. A 3-pyridinyloxymethyl substituent was also found to be equipotent as higher molecular weight analogs, and exhibited decreased CYP3A4 inhibition levels and improved pharmacokinetic properties.

Ketopiperazine 2 was designed from a previously published analog. Compound 2 was shown to be a novel, potent inhibitor of renin that, when administered orally, lowered blood pressure in a hypertensive double transgenic (human renin and angiotensinogen) mouse model. Compound 2 was further optimized to sub-nanomolar potency by designing an analog that addressed the S3 sub-pocket of the renin enzyme (16).

A convenient and rapid synthesis of 4‐(R)‐(naphthalen‐2‐yloxy)‐1‐(1‐phenyl‐(S)‐ethyl)‐pyrrolidin‐3‐(R)‐ol and 4‐(S)‐(naphthalen‐2‐yloxy)‐1‐(1‐phenyl‐(S)‐ethyl)‐pyrrolidin‐3‐(S)‐ol is disclosed. The reaction scheme is highlighted by the meso‐epoxidation of 1‐(1‐phenyl‐(S)‐ethyl)‐2,5‐dihydro‐1H‐pyrrole followed by addition of 2‐naphthol alkoxide to provide both expected diastereoisomers. Separation of the diastereoisomers by crystallization provided access to both diastereoisomers in modest yield without the employment of expensive chiral catalysts. X‐ray analysis of one of the diastereoisomers led to the unambiguous assignment of each diastereoisomer. These chiral pyrrolidine analogues should be useful as intermediates in natural product, combinatorial/parallel synthesis, and medicinal chemistry.

Factor Xa (FXa) has materialized as a key enzyme for the intervention of the blood coagulation cascade and for the development of new antithrombotic agents. FXa is the lone enzyme responsible for the production of thrombin and therefore is an attractive target for the control of thrombus formation. We have designed and synthesized a unique series of quinoxalinone FXa inhibitors. This series resulted in 3-[4-[5-((2S,6R)-2,6-dimethylpiperidin-1-yl)pentyl]-3-oxo-3,4-dihydroquinoxolin-2-yl]benzamidine (35) with 0.83 nM activity against FXa and excellent selectivity over similar serine proteases. An X-ray crystal structure of compound 35 bound to trypsin along with molecular modeling has led to a predicted binding conformation of compound 35 in FXa. Compound 35 has also been proven to be efficacious in vivo in both the rabbit veno-venous shunt and dog electrolytic injury models. In addition, it was shown that compound 35 did not significantly increase bleeding times in a rabbit model except at the highest doses and plasma concentrations were elevated in a dose dependent manner following a bolus dose and continuous intravenous infusion.

A rapid synthesis of a series of 6-alkyl substituted-5-(4′-amino-phenyl)-pyrimidine-2,4-diamines is described. These analogs were produced in good yields on moderate scale (ca. 8 g) without chromatography. Furthermore, the methodology described herein allows the production of 6-[ethyl, propyl, isopropyl, and isobutyl]-5-(4′-amino-phenyl)-pyrimidine-2,4-diamines in a more straightforward manner than previously disclosed.[1d] These novel compounds should aid in the structure-activity relationship analysis of current pyrimidines that possess anti-tumor and anti-malarial activities.

We previously demonstrated that selective inhibition of protein kinase Cθ (PKCθ) with triazinone 1 resulted in dose-dependent reduction of paw swelling in a mouse model of arthritis.1,2 However, a high concentration was required for efficacy, thus providing only a minimal safety window. Herein we describe a strategy to deliver safer compounds based on the hypothesis that optimization of potency in concert with good oral pharmacokinetic (PK) properties would enable in vivo efficacy at reduced exposures, resulting in an improved safety window. Ultimately, transformation of 1 yielded analogues that demonstrated excellent potency and PK properties and fully inhibited IL-2 production in an acute model. In spite of good exposure, twice-a-day treatment with 17l in the glucose-6-phosphate isomerase chronic in vivo mouse model of arthritis yielded only moderate efficacy. On the basis of the exposure achieved, we conclude that PKCθ inhibition alone is insufficient for complete efficacy in this rodent arthritis model.

Protein kinase Cθ (PKCθ) regulates a key step in the activation of T cells. On the basis of its mechanism of action, inhibition of this kinase is hypothesized to serve as an effective therapy for autoimmune diseases such as rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and psoriasis. Herein, the discovery of a small molecule PKCθ inhibitor is described, starting from a fragment hit 1 and advancing to compound 41 through the use of structure-based drug design. Compound 41 demonstrates excellent in vitro activity, good oral pharmacokinetics, and efficacy in both an acute in vivo mechanistic model and a chronic in vivo disease model but suffers from tolerability issues upon chronic dosing.

The formal total synthesis of the marine metabolite (+)-calyculin A is reported. The key steps involve (i) the use of Brown allylboration chemistry to control the relative and absolute stereochemistry of homoallylic alcohol arrays, thus setting eight of the desired stereocenters; (ii) Stille coupling methodology in the construction of the cyano tetraene unit of the natural product; and (iii) a modified Cornforth–Meyers approach to the synthesis of the oxazole fragment.Key words: calyculin, marine natural product, phosphatase inhibitor, total synthesis, palladium catalyzed coupling reactions, allylboration reactions, aldol reactions, spiroketal, Cornforth–Meyers oxazole reaction.

A small molecule factor VIIa inhibitor has recently been reported by the Ono Pharmaceutical Company. Herein, we outline an efficient and convergent, synthetic route that relies upon a palladium-catalyzed Stille coupling reaction as a key step for the synthesis of the inhibitor.

The synthesis and antithrombotic activity of a series of nonpeptide bicyclic thrombin inhibitors are described. We have explored the SAR around the P1' site. Modification of the P1' site has been found to affect potency and selectivity.

The synthesis and antithrombotic activity of a series of nonpeptide bicyclic thrombin inhibitors is described. We have explored the SAR with modifications to the P1 site. The introduction of arginine mimetics at the P1 site led to potent and selective thrombin inhibitors.

Peptidomimetic inhibitors of general structure 1 have been prepared. Optimization of the binding affinities of these compounds through variation of the P3 hydrophobic residue is described. Selected substituted bicylic lactams displayed interesting pharmacological profiles both in vitro and in vivo.

The development of benzothiazine-1,1-dioxide derivatives as a new structural class of potent endothelin receptor antagonists is described. Structure–activity relationships (SAR) revealed that PD164800 ( 1 ) is a potent antagonist of the ET A receptor subtype.

The design of potent and selective non-peptide antagonists of endothelin-1 (ET-1) and its related isopeptides are important tools defining the role of ET in human diseases. In this report we will describe the detailed structure-activity relationship (SAR) studies that led to the discovery of a potent series of butenolide ETA selective antagonists. Starting from a micromolar screening hit, PD012527, use of Topliss decision tree analysis led to the discovery of the nanomolar ET(A) selective antagonist PD155080. Further structural modifications around the butenolide ring led directly to the subnanomolar ETA selective antagonist PD156707, IC50's = 0.3 (ET(A)) and 780 nM (ET(B)). This series of compounds exhibited functional activity exemplified by PD156707. This derivative inhibited the ETA receptor mediated release of arachidonic acid from rabbit renal artery vascular smooth muscle cells with an IC50 = 1.1 nM and also inhibited the ET-1 induced contraction of rabbit femoral artery rings (ETA mediated) with a pA2 = 7.6. PD156707 also displayed in vivo functional activity inhibiting the hemodynamic responses due to exogenous administration of ET-1 in rats in a dose dependent fashion. Evidence for the pH dependence of the open and closed tautomerization forms of PD156707 was demonstrated by an NMR study. X-ray crystallographic analysis of the closed butenolide form of PD156707 shows the benzylic group located on the same side of the butenolide ring as the gamma-hydroxyl and the remaining two phenyl groups on the butenolide ring essentially orthogonal to the butenolide ring. Pharmacokinetic parameters for PD156707 in dogs are also presented.

Endothelin-1 is a potent vasoconstrictor which is thought to be involved in many human disease states. We have developed a series of indole non-peptide endothelin antagonists which display nanomolar receptor affinity. The representative compound from this series is PD 159433 ( 22 ), an ET A selective antagonist with an IC 50 of 2 nM. The discovery, synthesis and structure-activity relationships of this series of compounds are described.

Endothelin-1 is a potent vasoconstrictor that is thought to be involved in many human disease states. We have developed a series of indole non-peptide endothelin antagonists including PD 159110 ( 31 ), an ET A selective antagonist, and PD 159020 ( 37 ), a non-selective ET A /ET B antagonist. The discovery, synthesis, and structure-activity relationships of this series of compounds are described.

A series of 5-[[1-(4'-carboxybenzyl)imidazolyl]methylidene]hydantoins have been prepared and evaluated as in vitro and in vivo angiotensin II (Ang II) antagonists. Variation of substituents on the hydantoin ring leads to potent and selective Ang II antagonists with nanomolar IC50 values at the AT1 receptor and negligible affinity for the AT2 receptor. Preferred substituents include an n-butyl at R1 and an alkyl or heteroarylmethyl substituent at R2. The selection of the R2 substituent was guided in part by the calculation of its log P since a significant correlation was observed between CLOGP and AT1 binding affinity. The biphenyl tetrazole pharmacophore, common to a number of AT1 antagonists, could be replaced by, for example, a 4-carbomethoxyphenyl substituent resulting in potent Ang II antagonists both in vitro and in vivo. A representative compound of this series is 57, which reduced the mean arterial blood pressure of renal hypertensive rats by 40% at 30 mg/kg po and by 25% at 10 mg/kg po. In addition this compound was efficacious in the salt-deplete normotensive monkey model maximally decreasing blood pressure 27% at 10 mg/kg po. In summary, these compounds belong to a novel class of Ang II antagonists that lack the biphenyl tetrazole moiety yet display appreciable and long lasting oral activity.

Optimization of the ADME properties of a series of 2,4-diaminopyrimidine-5-carboxamide inhibitors of Sky kinase resulted in the identification of highly selective compounds with properties suitable for use as in vitro and in vivo tools to probe the effects of Sky inhibition.

Despite the success of anti-TNFα biologicals, there remains a significant unmet need for novel oral anti-inflammatory drugs for the treatment of rheumatoid arthritis and related diseases. Vigorous exploration of many potential targets for inhibition of, for example, pro-inflammatory cytokine production has led to efforts to find inhibitor leads targeting many enzymes including the p38α substrate kinase MK2. MK2 has a key role in the production of several pro-inflammatory cytokines, and studies with knockout animals and inhibitor leads support the promise of MK2 as an anti-inflammatory target. However, MK2 has additional biological roles such as in cell cycle checkpoint control, suggesting caution in the use of MK2 inhibitors for chronic non-life-threatening clinical indications such as inflammation. MK2 inhibitor lead identification and optimization efforts in several labs have resulted in a variety of potent and specific lead molecules, some of which display in-vivo activity. However, potency loss from enzyme to cell, and cell to in vivo, is commonly significant. Further, poor enzyme to cell potency correlations are also common for MK2 lead chemical series, suggesting uncontrolled confounding factors in lead inhibitor properties, or that the biological roles of MK2 and related enzymes may still be poorly understood. While further efforts in identification of MK2 inhibitors may yet yield viable drug leads, efforts to date suggest caution with this target.

A novel series of nonpeptide angiotensin II (AII) receptor antagonists containing a 1H-pyrrol-1-yl moiety at the 4-position of the imidazole have been developed. The pyrrole group occupies the same lipophilic pocket at the receptor as the chloro group in DuP 753 (68) and EXP 3174 (69) and the pentafluoro group in DuP 532 (70), respectively. The impetus for its selection came from bioisosteric considerations based on hydrophobic and electronic substituent constants. An extensive study of the structure-activity relationships revealed several highly potent AII receptor antagonists. An acyl substitution at the 2-position of the pyrrole ring improved activity, most notably in the in vivo rat model. In addition, the 2-substituted pyrrole compounds improved chemical stability toward extremely facile decarboxylation reaction associated with unsubstituted pyrrole analogues, thus facilitating development of these agents. The IC50's of 18, 20, and 42 (< 1 nM) were better than the reference compounds 69 and 70, respectively. These compounds were selective AII antagonists that compete at the AT1 receptor and showed no affinity at the AT2 receptor at concentrations up to 10 microM. Upon intravenous administration in a normotensive rat model, compound 18 inhibited the AII-induced responses with ED50 of 6 micrograms/kg per min. In a renal hypertensive rat model, the antihypertensive potency of compound 18, at a dose of 10 mg/kg, was very similar to those 68 and 69, respectively. Compound 18 demonstrated a dose-related (3-30 mg/kg) decrease in blood pressure that was sustained for greater than 24 h. On the basis of its profile, compound 18, designated as CI-996, has been selected for in-depth studies. The design, synthesis, in vitro, and in vivo structure-activity relationships are described.

Syntheses of radiolabeled, fluorescent and biotinyl probes with highly selective affinity for the angiotensin AT 2 receptor are described. The binding affinities at AT 2 and AT 1 receptors are reported.

Two concise enantioselective syntheses of the C(15)–C(25) spiroketal unit of calyculin A, using derivatives of allyldiisopinocampheylborane efficieintly to control 1,2- and 1,3-diol stereochemistries, are reported.

An enantioselective and geometrically selective synthesis of the C(1)–C(14) tetraene nitrile unit of calyculin A, using aldol chemistry with (+)-(E)-diisopinocampheylborane and Stille coupling, is described.

(–)-B-[3-(Diisopropylaminodimethylsilyl)allyl]diisopinocampheylborane and Cornforth–Meyers chemistry, and Evans alkylation were employed to construct the C(26)–C(37) amide–oxazole unit of calyculin A.

Peptidomimetic inhibitors of thrombin lacking the important Ser195–carbonyl interaction have been prepared. The binding energy lost after the removal of the activated carbonyl was recaptured through a series of modifications of the P1 residues of the bicyclic lactam inhibitors. Selected substituted compounds displayed useful pharmacological profiles both in vitro and in vivo.

The formal total synthesis of the marine metabolite (+)-calyculin A is reported. The key steps involve (i) the use of Brown allylboration chemistry to control the relative and absolute stereochemis...

The potency and selectivity of a previous series of low molecular weight thrombin inhibitors were improved through modifications of the P1 and P3 residues. Introduction of diphenyl substituted sulfonamides in the P3 moiety led to highly efficacious compounds. By correctly selecting the combination of P1 and P3 residues, high levels of potency, selectivity and in vivo efficacy were obtained.

Novel 2,4-diaminopyrimidine-based small molecule renin inhibitors are disclosed. Through high throughput screening, parallel synthesis, X-ray crystallography, and structure based drug design, we have developed the first non-chiral, non-peptidic, small molecular template to possess moderate potency against renin. The designed compounds consist of a novel 6-ethyl-5-(1,2,3,4-tetrahydroquinolin-7-yl)pyrimidine-2,4-diamine ring system that exhibit moderate potency (IC(50): 91-650 nM) against renin while remaining 'Rule-of-five' compliant.

Inhibition of renin enzymatic activity by a series of ketopiperazine-based compounds containing a C6 benzyloxymethyl substituent correlated with a +(pi+sigma) effect. A 3-pyridinyloxymethyl substituent was also found to be equipotent as higher molecular weight analogs, and exhibited decreased CYP3A4 inhibition levels and improved pharmacokinetic properties.

Herein, we report on the identification of three potent glycine and related amino acid-based series of FXa inhibitors containing a neutral P1 chlorophenyl pharmacophore. A X-ray crystal structure has shown that constrained glycine derivatives with optimized N-substitution can greatly increase hydrophobic interactions in the FXa active site. Also, the substitution of a pyridone ring for a phenylsulfone ring in the P4 sidechain resulted in an inhibitor with enhanced oral bioavailability.