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Succinyl hydroxamates 1 and 2 are disclosed as novel series of potent and selective inhibitors of procollagen C-proteinase (PCP) which may have potential as anti-fibrotic agents. Carboxamide 7 demonstrated good PCP inhibition and had excellent selectivity over MMPs involved in wound healing. In addition, 7 was effective in a cell-based model of collagen deposition (fibroplasia model) and was very effective at penetrating human skin in vitro. Compound 7 (UK-383,367) was selected as a candidate for evaluation in clinical studies as a topically applied, dermal anti-scarring agent.

Thrombin-activatable fibrinolysis inhibitor (TAFI) has emerged as a key link between the coagulation and fibrinolysis cascades and represents a promising new target for the treatment of thrombosis. A novel series of imidazolepropionic acids has been designed that exhibit high potency against activated TAFI (TAFIa) and excellent selectivity over plasma carboxypeptidase N (CPN). Structure activity relationships suggest that the imidazole moiety plays a key role in binding to the catalytic zinc of TAFIa, and this has been supported by crystallographic studies using porcine pancreatic carboxypeptidase B as a surrogate for TAFIa. The SAR program led to the identification of 21 (TAFIa Ki = 10 nM, selectivity TAFIa/CPN > 1000) as a candidate for clinical development. Compound 21 exhibited antithrombotic efficacy in a rabbit model of venous thrombosis, yet had no effect on surgical bleeding in the rabbit. In addition, 21 exhibited an excellent preclinical and clinical pharmacokinetic profile, characterized by paracellular absorption, low clearance, and a low volume of distribution, fully consistent with its physicochemical properties of low molecular weight (MW = 239) and high hydrophilicity (log D = -2.8). These data indicate 21 (UK-396,082) has potential as a novel TAFIa inhibitor for the treatment of thrombosis and other fibrin-dependent diseases in humans.

6-Cyclohexyl-N-hydroxy-3-(1,2,4-oxadiazol-5-yl)hexanamides were previously disclosed as inhibitors of procollagen C-proteinase (PCP) culminating in the identification of amide 1. Our objective was to discover a second inhibitor that would have improved affinity for PCP and to optimize properties for transepidermal delivery (TED) to intact skin. Further investigation of this template identified a number of potent PCP inhibitors (IC50 values of 2-6 nM) with improved TED flux. Sulfonamide 56 had excellent PCP enzyme activity when measured with a peptide substrate (Ki 8.7 nM) or with the endogenous substrate procollagen (IC50 3.4 nM) and demonstrates excellent selectivity over MMPs involved in wound healing (10 000-fold). In the fibroplasia model, 56 inhibited deposition of insoluble collagen by 76 +/- 2% at 10 microM and was very effective at penetrating human skin in vitro with a TED flux of 1.5 microg/cm2/h, which compares favorably with values for agents that are known to penetrate skin well in vivo. Based on this profile, 56 (UK-421,045) was selected as a candidate for further preclinical evaluation as a topically applied, dermal anti-scarring agent.

Tumour necrosis factor-alpha (TNF-alpha) is a potent pro-inflammatory agent produced primarily by activated monocytes and macrophages. TNF-alpha is synthesized as a precursor protein of M(r) 26,000 (26K) which is processed to a secreted 17K mature form by cleavage of an Ala-Val bond between residues 76-77. The enzyme(s) responsible for processing pro-TNF-alpha has yet to be identified. Here, we describe the capacity of a metalloproteinase inhibitor, GI 129471, to block TNF-alpha secretion both in vitro and in vivo. The inhibition is specific to TNF-alpha; the production of other secreted cytokines, such as the interleukins IL-1 beta, IL-2, or IL-6, is not inhibited. The mechanism of inhibition occurs at a post-translational step in TNF-alpha production. Our data suggest that TNF-alpha processing is mediated by a unique Zn2+ endopeptidase which is inhibited by GI 129471 and would represent a novel target for therapeutic intervention in TNF-alpha associated pathologies.

Optimisation of NK 2 receptor affinity in a series of sulfur derivatives resulted in the identification of Highly potent 5-fluoroindol-3-ylethyl[4-(phenylsulfinyl methyl])piperidines. Further structure activity analysis led to GR 159897 an NK 2 receptor antagonist which potently blocks agonist-induced bronchoconstriction in the guinea-pig when administered by peripheral and oral routes.

A deletion - optimization strategy based on an initial heptapeptide lead structure 1 led to potent and selective neurokinin NK2 antagonists 5 (pKB=9.3) and 9 (pKB=7.9) of substantially reduced molecular size. Tetrapeptide 5 (0.1 μmol/Kg i.v.) potently inhibits NK2 agonist-induced bronchoconstriction in guinea-pigs. Whilst less potent than 5 in vivo, the dipeptoid 9 (5 μmol/Kg i.v.) had a significantly longer biological half-life (> 2 h), and provides a potential lead towards non-peptide analogues.

Allylic phosphine oxides are epoxidised anti selectively by m-CPBA, but this selectivity can be reversed if the allylic phosphine oxide is also an allylic alcohol.

Incorporation of D-Pro9 into substance P related peptides is known to enhance neurokinin NK-2 receptor agonist potency and selectivity with respect to other neurokinin receptors. We now report that replacement of D-Trp9 by D-Pro9 in the nonselective neurokinin antagonist [Arg5,D-Trp7,9, Nle11]-SP(5-11) gave a partial agonist with NK-2 receptor selectivity. Further incorporation of Pro10 provided the weak but selective NK-2 antagonist Arg-Ala-D-Trp-Phe-D-Pro-Pro-Nle-NH2 (compound 4; NK-2 pKB = 5.9; NK-1 pKB = 4.7; NK-3 pKB less than 4.6). Addition of a suitable lipophilic N-terminal substituent (e.g. Boc, PhCO, cyclohexylcarbonyl) to this compound greatly enhanced NK-2 antagonist activity (compound 10, GR 83074; NK-2 pKB = 8.2), and combined with further optimization of the N-terminal amino acids, provided the extremely potent and selective NK-2 antagonist PhCO-Ala-Ala-D-Trp-Phe-D-Pro-Pro-Nle-NH2 (compound 34, GR 94800; NK-2 pKB = 9.6; NK-1 pKB = 6.4; NK-3 pKB = 6.0). Compounds of this class produced a potent inhibition of NK-2 agonist-induced bronchoconstriction in the anaesthetized guinea-pig.

The syntheses of some 1-[(3,4-dichlorophenyl)acetyl]-2- [(alkylamino)methyl]piperidines and their activities as kappa-opioid receptor agonists are described. Selected structural modifications are made to the basic moiety and at the 2-, 3-, 4-, 5-, and 6-positions on the piperidine nucleus to enable structure-activity relationships to be delineated. As a result, some highly potent and selective kappa-receptor agonists have been identified. In particular, this has been achieved by introduction of oxygen-containing functionality into the 4-position of the piperidine nucleus or the 3-position of the pyrrolidinylmethyl side chain. Thus, 1-[(3,4-dichlorophenyl)acetyl]- 2-[[1-(3-oxopyrrolidinyl)]methyl]piperidine (10) possesses high activity in the rabbit vas deferens (LVD, kappa-specific tissue) (IC50 = 0.20 nM) and is a potent antinociceptive agent, as determined by the mouse acetylcholine-induced abdominal constriction test (MAC) (ED50 = 0.06 mg/kg, sc). The spirocyclic analogue 8-[(3,4-dichlorophenyl)acetyl]-7-(1-pyrrolidinylmethyl)-1,4-dio xa-8- azaspirol4.5]decane (39) showed exceptionally potent activity: LVD, IC50 = 0.10 nM; MAC, ED50 = 0.001 mg/kg, sc. Both 10 and 39 displayed high selectivity for kappa-opioid receptors over both mu- and delta-opioid receptor subtypes.

A series of trans-3-(6- and 7-substituted-decahydro-4a-isoquinolinyl)phenols and trans-3-(octahydro-4a-isoquinolinyl)phenols have been synthesized as potential opioid analgesics. Using a combination of in vitro and in vivo test systems, the receptor profiles of selected compounds have been assessed and in some instances distinguish between mu- and kappa-receptor agonists. In general, introduction of a 6-exocyclic methylene group into the trans-3-(decahydro-4a-isoquinolinyl)phenol system enhanced both antinociceptive activity and kappa-opioid receptor selectivity. For each series, analogues bearing an N-cyclopropylmethyl substituent exhibited greater kappa-receptor selectivity while N-methyl derivatives showed greater mu-receptor selectivity. The 7-substituted compounds (3b) were significantly less potent antinociceptive agents than their 6-substituted counterparts (3a), the octahydroisoquinoline analogues exhibiting intermediate activity. The axial 8-methyl-6-exocyclic methylene isoquinoline (20) is the most potent compound in the mouse abdominal constriction assay (ED50 = 0.05 mg/kg sc), whereas the equatorial 8-methyl isomer (16) was significantly less potent (ED50 = 3.3 mg/kg sc).

Succinyl hydroxamates 1 and 2 are disclosed as novel series of potent and selective inhibitors of procollagen C-proteinase (PCP) which may have potential as anti-fibrotic agents. Carboxamide 7 demonstrated good PCP inhibition and had excellent selectivity over MMPs involved in wound healing. In addition, 7 was effective in a cell-based model of collagen deposition (fibroplasia model) and was very effective at penetrating human skin in vitro. Compound 7 (UK-383,367) was selected as a candidate for evaluation in clinical studies as a topically applied, dermal anti-scarring agent.

Acylation of Ph2P(O) Me with a lactone gives a Horner–Wittig intermediate with a Z-double bond protected as a Diels–Alder adduct with furan and hence (Z)-penta-2,4-dien-1-ol. Substituted (E)-penta-2,4-dien-1-ols are available by a more general route involving addition of enals to phosphine oxides, a regiochemically controlled allylic alcohol transposition, and a Horner–Wittig reaction. The geometry of only one double bond can be controlled.

A generic macrocyclic peptide structure 2 was designed as a potential inhibitor of a range of proteinases, by using as a basis for the design the known structures of a series of enzyme-inhibitor complexes. The macrocyclic nature of the target 2 was chosen so as to reduce the entropic advantage in the hydrolytic enzymatic step, and thereby to inhibit the function of the enzyme. The nature of the linking group was identified as a benzoxazole by molecular modeling, so as to preserve the recognized conformation of the peptide chain. The specificity of the potential inhibitor was tuned by variation of the P(1) group (by incorporating phenylalanine, aspartic acid, or lysine), to allow recognition by different enzyme classes. The targets were prepared from the bis-amino acid derivative 5, itself prepared using the Pd-catalyzed coupling of an organozinc reagent with the iodobenzothiazole 7 and subsequent macrocyclization of the open-chain derivatives 22-24 using HATU. None of the macrocylic compounds 25, 28-30, and 32 inhibited their target enzymes. NMR and MS studies on the interaction of macrocycle 29 and chymotrypsin established that compound 29 was in fact a substrate of the enzyme. This result indicated that while the design had been partially successful in identifying a compound that bound, the reduction in entropic advantage due to its macrocyclic nature was not sufficient to allow 29 to act as an inhibitor.

Potent and selective inhibitors of thrombin were sought based on the (R)-Phe-Pro-Arg sequence. The objective was to generate similar binding interactions to those achieved by potent competitive inhibitors of the argatroban type, so eliminating the need for covalent interaction with the catalytic serine function, as utilized by aldehyde and boronic acid type inhibitors. Improving the S(1) subsite interaction by substitution of arginine with a 4-alkoxybenzamidine residue provided potent lead 2 (K(i) = 0.37 nM). Though an amide bond, which H-bonds to the active site, is lost, modeling indicated that a new H-bond is generated between the alkoxy oxygen atom and the catalytic Ser-195 hydroxyl group. Substitution of the benzamidine system by 1-amidinopiperidine then gave compound 4, which provided a further gain in selectivity over trypsin. However, previous work had shown that these compounds were likely to be too lipophilic (Log D +0.4 and +0.2, respectively) and to suffer rapid hepatic extraction, presumably via biliary elimination. Accordingly, both proved short-acting when administered intravenously to rats and showed poor activity when given intraduodenally. The aim was then to reduce lipophilicity below a log D of -1.2, which in a previously reported series had been effective in preventing rapid clearance. It was anticipated that compounds of this type would rely on the cation selective paracellular route of absorption from the gastrointestinal tract. Potent polar analogues with selectivity1000 over trypsin were obtained. The best in vivo activity was shown by compound 12. However, in the final analysis, its oral bioavilability proved poor, relative to analogues with similar physicochemical properties derived from argatroban, consistent with the hypothesis that molecular shape is an additional important determinant of paracellular absorption.

Systematic modification of the presumed P1 side chain in a series of (carboxyalkyl)amino-based inhibitors of matrix metalloproteinases enabled identification of the 2-(1,3-dihydro-1,3-dioxo-2H-benz [f]isoindol-2-yl)ethyl group as a preferred substituent imparting potent inhibition of the enzymes collagenase and gelatinase. It was subsequently found that the P2'-P3' residues in this series could be replaced by small non-peptide residues, while maintaining inhibitory potency. The imide group in this series of compounds can undergo autocatalytic hydrolysis under neutral conditions

Collagenase is a zinc-dependent endoproteinase and is a member of the matrix metalloproteinase (MMP) family of enzymes. The MMPs participate in connective tissue remodeling events and aberrant regulation has been associated with several pathologies. The 2.4 angstrom resolution structure of the inhibited enzyme revealed that, in addition to the catalytic zinc, there is a second zinc ion and a calcium ion which play a major role in stabilizing the tertiary structure of collagenase. Despite scant sequence homology, collagenase shares structural homology with two other endoproteinases, bacterial thermolysin and crayfish astacin. The detailed description of protein-inhibitor interactions present in the structure will aid in the design of compounds that selectively inhibit individual members of the MMP family. Such inhibitors will be useful in examining the function of MMPs in pathological processes.

A concise synthesis of the 6-oxamorphinan ring system has been designed which allows introduction of functionality at the 10-position. This has provided a series of 10-methylene-, 10-oxo-, and 10α-methyl-6-oxamorphinans, (24a–e), (25a–d), and (26a–c) respectively. The enamine 8a-(3-methoxyphenyl)-6-methyl-3,4,6,7,8,8a-hexahydro-1H-pyrano[4,3-c]pyridine (4a) is converted in three steps, via trans-8a-(3-methoxyphenyl)-6-methyloctahydropyrano[4,3-c]pyridine-5α-carbonitrile (7a) and the corresponding 5α-acetyl derivative (9a), to the tetracyclic 10-methylene-6-oxamorphinan (11a). Oxidative cleavage of the 10-exocyclic methylene group of (11a) provides entry into the 10-oxo series. The antinociceptive activity and opioid receptor profiles of (24a–e), (25a–d), and (26a–c) have been evaluated and structure–activity relationships are discussed.

Allylic rearrangement of substitued 2-hydroxyalk-3-en-1-yl(diphenyl)phosphine oxides to 4-hydroxyalk-2-en-1-yl(diphenyl)phosphine oxides can be performed with total regio- and reasonable stereochemical control. Alternatively, the reduction of substituted 4-diphenylphosphinoylbut-2-en-1 -ones shows remarkable 1,4-diastereoselectivity. All these reactions are directed by the diphenylphosphinoyl (Ph2PO) group.

A concise synthesis of the 6-oxamorphinan ring system has been designed which allows introduction of functionality at the 10-position. This has provided a series of 10-methylene-, 10-oxo-, and 10α-methyl-6-oxamorphinans, (24a–e), (25a–d), and (26a–c) respectively. The enamine 8a-(3-methoxyphenyl)-6-methyl-3,4,6,7,8,8a-hexahydro-1H-pyrano[4,3-c]pyridine (4a) is converted in three steps, via trans-8a-(3-methoxyphenyl)-6-methyloctahydropyrano[4,3-c]pyridine-5α-carbonitrile (7a) and the corresponding 5α-acetyl derivative (9a), to the tetracyclic 10-methylene-6-oxamorphinan (11a). Oxidative cleavage of the 10-exocyclic methylene group of (11a) provides entry into the 10-oxo series. The antinociceptive activity and opioid receptor profiles of (24a–e), (25a–d), and (26a–c) have been evaluated and structure–activity relationships are discussed.

The title compounds (3) were synthesised by stereospecific [1,3] rearrangement, controlled by the Ph 2 PO group, from single isomers of the Horner-Wittig adducts (1)

2,5-Dimethylhex-4-en-3-one, E-6-methylhept-2-en-4-one, E-7-methyloct-4-en-3-one, ar-turmerone, and E-7-oxo-act-5-enoic acid were synthesized regiospecifically viaα-phenylthio ketones from bisphenylthio carbanions and aldehydes.

Enones not available from aldol condensations may be synthesised regio-specifically via α-(phenylthio)ketones: the title compounds have been made by this route.

4-Hydroxy-2-alkenyldiphenylphosphine oxides, prepared by a phosphorus-controlled allylic rearrangement, give dianions and hence α-hydroxydienes (substituted penta-2,4-dienols) by the Horner-Wittig reaction.

All four isomers of substituted 3-alkylthio-4-hydroxybutenes have been synthesised: both the geometry of the double bond and the relative stereochemistry of the two chiral centres are controlled.

The title compounds were epoxidised by m-chloroperbenzoic acid with high stereoselectivity induced by the Ph2PO or hydroxyl groups.

The synthesis of a series of novel cis- and trans-3-(octahydro-1H-pyrano[4,3-c]pyridin-8a-yl)phenols (13a–1), (15a, b), (20a–d), (21a–e) and the trans-3-(octahydro-1H-thiopyrano[4,3-c]pyridin-8a-yl)phenol (26) is described. Alkylation of 1-methyl-4-(3-methoxyphenyl)-1,2,3,6-tetrahydropyridine (7) with 2-chloro-1-(chloromethoxy)ethane or 2-chloro-1-(chloromethoxy)propane, and subsequent cyclization, generated the bicyclic enamines (9a) and (9b) respectively. Hydrogenation of (9a, b) under neutral conditions provided the trans-fused octahydropyrano[4,3-c]pyridines (10a), (16a), and (17a), whereas hydrogenation of (9a) in acidic media gave the corresponding cis-fused system (11a). The trans-fused octahydrothiopyrano[4,3-c]pyridine (23) was synthesized via the analogous enamine (22). Selected N-substituents were introduced via a vinyl chloroformate N-demethylation/re-alkylation sequence and subsequent O-demethylation afforded the title phenols. The antinociceptive activity and opioid receptor profile of these compounds has been determined and structure activity relationships are discussed.

The synthesis of a series of novel trans-3-(octahydro-2H-pyrano[2,3-c]pyridin-4a-yl)phenols (12a–g), (20a–c), (21), (22) and trans-3-(octahydro-1H-pyrano[3,4-c]pyridin-4a-yl) phenols (28a, b), (34) is described. Construction of the pyrano[2,3-c]pyridines is achieved via annulation of the pyran ring onto the arylpiperidin-3-ones (6) and (14)(R = CO2Ph). The pyrano[3,4-c]pyridines are synthesized by application of metallated enamine chemistry to 1-methyl-4-(3-methoxyphenyl)1,2,3,6-tetrahydropyridine (4) and proceeds via the novel 2-oxa-8-azabicyclo[3.3.1 ] nonane (23) and the bicyclic enamines (24) and (29). Manipulation of this general methodology has afforded a number of structural variants bearing strategic substitutions in the pyran ring as well as alternative N-groups. The antinociceptive activity and opioid receptor profile of these compounds has been determined and structure-activity relationships are discussed.

Allylic phosphine oxides are epoxidised anti selectively by m-CPBA, but this selectivity can be reversed if the allylic phosphine oxide is also an allylic alcohol.

Regioselective ring-openings of epoxy alcohols bearing a diphenylphosphinoyl ( Ph2PO ) group give diols which can undergo stereospecific Horner–Wittig elimination. This method was used to make allylic alcohols, unsaturated β-hydroxy sulfides, homoallylic alcohols and unsaturated amino acids, with control over their absolute (R,S), relative (syn,anti) and geometrical (E,Z) stereochemistry.

The synthesis of a series of novel trans-3-(octahydro-2H-pyrano[2,3-c]pyridin-4a-yl)phenols (12a–g), (20a–c), (21), (22) and trans-3-(octahydro-1H-pyrano[3,4-c]pyridin-4a-yl) phenols (28a, b), (34) is described. Construction of the pyrano[2,3-c]pyridines is achieved via annulation of the pyran ring onto the arylpiperidin-3-ones (6) and (14)(R = CO2Ph). The pyrano[3,4-c]pyridines are synthesized by application of metallated enamine chemistry to 1-methyl-4-(3-methoxyphenyl)1,2,3,6-tetrahydropyridine (4) and proceeds via the novel 2-oxa-8-azabicyclo[3.3.1 ] nonane (23) and the bicyclic enamines (24) and (29). Manipulation of this general methodology has afforded a number of structural variants bearing strategic substitutions in the pyran ring as well as alternative N-groups. The antinociceptive activity and opioid receptor profile of these compounds has been determined and structure-activity relationships are discussed.

The synthesis of a series of novel cis- and trans-3-(octahydro-1H-pyrano[4,3-c]pyridin-8a-yl)phenols (13a–1), (15a, b), (20a–d), (21a–e) and the trans-3-(octahydro-1H-thiopyrano[4,3-c]pyridin-8a-yl)phenol (26) is described. Alkylation of 1-methyl-4-(3-methoxyphenyl)-1,2,3,6-tetrahydropyridine (7) with 2-chloro-1-(chloromethoxy)ethane or 2-chloro-1-(chloromethoxy)propane, and subsequent cyclization, generated the bicyclic enamines (9a) and (9b) respectively. Hydrogenation of (9a, b) under neutral conditions provided the trans-fused octahydropyrano[4,3-c]pyridines (10a), (16a), and (17a), whereas hydrogenation of (9a) in acidic media gave the corresponding cis-fused system (11a). The trans-fused octahydrothiopyrano[4,3-c]pyridine (23) was synthesized via the analogous enamine (22). Selected N-substituents were introduced via a vinyl chloroformate N-demethylation/re-alkylation sequence and subsequent O-demethylation afforded the title phenols. The antinociceptive activity and opioid receptor profile of these compounds has been determined and structure activity relationships are discussed.