Abstract: A biologically pure culture of microorganisms capable of converting RS-&agr;-piperazinecarboxamides into the corresponding R-&agr;-piperazinecarboxylic acid. R-&agr;-piperazinecarboxamides is the only nitrogen source.

Abstract: A method for preparing a chiral beta amino acid or its corresponding esters which comprises contacting a racemic beta amino acid, an acyl donor and Penicillin G acylase enzyme under conditions appropriate to stereoselectively acylate one enantiomer of the racemic beta amino acid to its corresponding N-acylated derivative whereby the opposite enantiomer of the beta amino acid is retained in enantiomerically enriched form.

Abstract: A propargylic alcohol, enriched in the (R)-enantiomer, has the formula wherein R is C1-4 alkoxy, halogen, or C1-4 alkyl optionally substituted by OH or halogen. This is prepared by the steps of: (a) enantioselective (R)-esterification of the racemic alcohol using any acyl donor and a first enzyme; (b) removal of the untreated (S)-alcohol; and (c) enantioselective hydrolysis of the (R)-ester, using a second enzyme.

Abstract: The invention provides an efficient method of producing optically active N-benzyl-3-pyrrolidinol by an enzymatic reaction stereoselectively reducing N-benzyl-3-pyrrolidinone. The invention consists in a method of producing optically active N-benzyl-3-pyrrolidinol which comprises a step of obtaining a reaction mixture by treating N-benzyl-3-pyrrolidinone with cells or a culture of a microorganism, or a material derived therefrom, and a step of recovering optically active N-benzyl-3-pyrrolidinol from said reaction mixture, in which method said microorganism mentioned above is a microorganism belonging to the genus Dipodascus, Debaryomyces, Cryptococcus, Pichia, Rhodosporidium, Trichosporon, Micrococcus, Komagataella, Ogataea or Zygosaccharomyces.

Abstract: A process for preparing optically active primary and secondary heteroatom-substituted amines from the corresponding racemates, which comprises a) enantioselective acylation of a racemic heteroatom-substituted amine with an ester whose acid component carries a fluorine, nitrogen, phosphorus, oxygen or sulfur atom in the vicinity of the carbonyl carbon, in the presence of a hydrolase, b) separation of the mixture of optically active heteroatom-substituted amine and optically active acylated heteroatom-substituted amine to obtain one enantiomer of the heteroatom-substituted amine, c) if required isolation of the other enantiomer of the heteroatom-substituted amine from the acylated heteroatom-substituted amine by amide cleavage.

Abstract: Optically active cis-1,3-cyclohexanedicarboxylic acid monoesters of >90% enantiomeric excess (ee) and methods of preparing the monoesters are described. One method contacts a cis-1,3-cyclohexanedicarboxylic acid diester with a lipase under aqueous conditions to enantioselectively produce the optically active cis-1,3-cyclohexanedicarboxylic acid monoester. Another method reacts a mixture of cis- and trans-1,3-cyclohexanedicarboxylic acids under conditions sufficient to form a cis-cyclic anhydride, esterifies the cis-cyclic anhydride to produce a cis-1,3-cyclohexanedicarboxylic acid diester and then contacts under aqueous conditions the diester with a lipase to enantioselectively produce the optically active cis-1,3-cyclohexanedicarboxylic acid monoester.

Abstract: This invention relates to crystalline pharmaceutically acceptable salts of an alpha 1a adrenergic receptor antagonist, Compound A, which are useful in the treatment of benign prostatic hyperplasia. Pharmaceutical compositions employing the crystalline salts, and processes for making and using the crystalline salts and pharmaceutical compositions of Compound A are also disclosed. This invention further relates to a process for obtaining enantiomerically pure intermediate useful for the synthesis of end product alpha 1a adrenergic receptor antagonists. The end product compounds are useful for the treatment of benign prostatic hyperplasia and for relaxing lower urinary tract tissue. The invention also relates to a process for preparing a class of dihydropyrimidinone compounds of which Compound A is a member, wherein the process involves deprotonating a dihydropyrimidinone compound and then coupling the deprotonated derivative with a primary amine.

Abstract: The present invention relates to two novel microorganisms, Acinetobacter baumanni WT-50/50-4A (ATCC 202144) and Serratia marcescens WT-L-4A1(RED) (ATCC 202145) characterized by 4-hydroxyproline epimerase activity. The compounds trans-4-hydroxy-L-proline (THLP) or cis-4-hydroxy-D-proline (CHDP) are converted with this epimerase activity to a mixture of THLP and CHDP. Additionally, the compounds trans-4-hydroxy-D-proline (THDP) or cis-4-hydroxy-L-proline (CHLP) are converted with this epimerase activity to a mixture of THDP and CHLP.

Abstract: A process for preparing an optically active (S)-&agr;-aryl propionic acid, by hydrolyzing a racemic thioester of &agr;-aryl propionic acid at various temperature in different aqueous organic solvents in the presence of an (S)-stereoselective lipase to form an (S)-&agr;-aryl propionic acid product, while the unreacted (R)-thioester of &agr;-aryl propionic acid can be converted to the corresponding (S)-thioester of &agr;-aryl propionic acid via a racemization reaction by adding a base as the catalyst in the solution and then hydrolyzing by the lipase described as above so that the (S)-&agr;-aryl propionic acid can be obtained theoretically at a conversion of 100% and with high optical purity.

Abstract: The present invention provides a novel process for producing known optically active amines and optically active acylated amines by: a) in a first step, reacting racemic amines with esters, in the presence of hydrolases and possibly a diluent; b) in a second step, separating the reaction mixture into (S)-amine and acylated (R)-amine; and c) optionally in a third step releasing (R)-amine from acylated (R)-amine by treatment with an acid or base, possibly in the presence of a diluent. The optically active amines can be employed as intermediates for preparing pharmaceuticals and crop protection agents.

Abstract: An industrially advantageous production method of an optically active alcohol useful for cosmetics and medical supplies or production intermediates thereof using an esterase having an ability to selectively hydrolyze an optically active sphingoid compound.

Abstract: The invention relates to a process for the preparation of (−)-3,4-trans-compounds involving an enzymatic hydrolysis. These compounds and their salts are useful in the treatment of bone loss, hyperlipoproteinaemia, hypertriglyceridaemia, hyperlipidaemia, or hypercholes-terolaemia or arteriosclerosis or in anticoagulative treatment.

Abstract: The invention relates to a method and an apparatus for carrying out a treatment in the presence of centrifugal force. The treatment may be a physical or a chemical treatment. For this purpose the first and second phase are brought into contact with each other. The second phase comprises a phase soluble in the first phase and a third phase dispersed in the soluble phase. According to the invention at least one liquid phase is supplied continuously to a chamber for treatment (2) with a course of treatment while the third phase, which is a non-aggregating phase, is dispersed finely over the breadth of the course of treatment by the first phase.

Abstract: A process for preparing cis-(1S,2R)-indanediol is disclosed. The process comprises (A) fermenting a culture medium containing a yeast strain selected from the group consisting of Trichosporon cutaneum MY 1506 (ATCC 74440) and mutants thereof and 1,2-indanedione to form cis-(1S,2R)-indanediol; and (B) recovering cis-(1S,2R)-indanediol from the culture medium. A process for preparing (1S)-amino-(2R)-indanol from the recovered cis-(1S,2R)-indanediol via the Ritter reaction is also disclosed.

Abstract: An optically active alcohol substituted with one or more halogen atoms, such as optically active 4-halo-3-hydroxybutyrate esters, is efficiently synthesized by using a secondary alcohol dehydrogenase and an alcohol as a substrate accompanied by the renaturing of NADH by asymmetrical reduction of a halogen-substituted ketone such as 4-haloacetoacetate esters at low temperature. By performing the reaction at low temperature, the toxicity of a halogen-substituted ketone such as 4-haloacetoacetate esters and of the optically active alcohol such as 4-halo-3-hydroxybutyrate esters, is diminished. In this way, the accumulated concentration of an optically active alcohol substituted with one or more halogen atoms, such as 4-halo-3-hydroxybutyrate esters, may be increased while retaining the high stereoselectivity of the secondary alcohol dehydrogenase.

Abstract: A process for resolution of a mixture of dihydroxydihydroindene enantiomers comprising treating the mixture of enantiomers with a Pseudomonas putida species microorganism.Resolved dihydroxydihydroindenes are valuable intermediates for the synthesis of biologically active compounds such as pharmaceuticals and agrochemicals.

Abstract: There is provided a process for producing an optically active N-substituted azetidine-2-carboxylic acid compound represented by the formula (2): ##STR1## by contacting a corresponding N-substituted azetidine-2-carboxylic acid ester of formula (2) with an enzyme derived from a microorganism selected from Arthrobacter SC-6-98-28 strain, Arthrobacter sp. ATCC21908 strain, Chromobacterium SC-YM-1 strain, and a mutant thereof. A process is also provided for preparing an optically active azetidine-2-carboxylic acid by eliminating the N-substituent of a N-substituted azetidine-2-carboxylic acid ester of formula (2).

Abstract: Process for obtaining an enantiomerically enriched N-acylazetidine-2-carboxylic acid, wherein a racemic N-acylazetidine-2-carboxylic acid ester is contacted with an enzyme that displays enantiospecificity to form enantiomerically enriched N-acylazetidine-2-carboxylic acid.

Abstract: A process for producing an [S,S]-ethylenediamine-N,N'-disuccinic acid alkali metal salt which comprises reacting fumaric acid with ethylenediamine in an aqueous medium in the presence of an ion of at least one metal selected from the group consisting of alkaline earth metals and transition metals by the action of ethylenediamine-disuccinic acid ethylenediamine lyase of microorganism origin, adding an alkali hydroxide to a reaction product mixture thereby to separate and recover the metal ion as an insoluble precipitate, and obtaining an [S,S]-ethylenediamine-N,N'-disuccinic acid alkali metal salt.

Abstract: 2-Aminopropane is used as the amine donor in the stereoselective synthesis of a chiral amine from a ketone with a transaminase. In a typical embodiment, (S)-1-methoxy-2-aminopropane is prepared by bringing methoxyacetone into contact with a transaminase in the presence of 2-aminopropane as an amine donor until a substantial amount of methoxyacetone is converted to (S)-1-methoxy-2-aminopropane and 2-aminopropane is converted to acetone. In a second embodiment, L-alanine is prepared by bringing pyruvic acid into contact with a transaminase in the presence of 2-aminopropane as an amine donor.

Abstract: A process for the stereoselective microbial reduction of compound of formula II to compound of formula I ##STR1## comprising adding compound of formula II to a medium, medium and buffer, medium and solvent, or medium and a mixture of buffer and solvent containing a microorganism, preferably Rhodococcus fascians ATCC No. 202210 or fungal isolate Geotrichum candidum ATCC No. 74487, incubating the resulting mixture, and isolating a hydroxy compound of formula I, is described. The compound of formula I is a serum cholesterol lowering agent.

Abstract: The present invention relates to a process for producing optically active 3-quinuclidinol or derivatives, wherein a racemic 3-quinuclidinol ester represented by the general formula (I): ##STR1## wherein R represents a straight-chain or branched alkyl group, and (H.sup.+) represents that said ester may be in the form of a salt formed with a mineral acid or an organic acid, is reacted with a microorganism belonging to the genus Aspergillus, Rhizopus, Candida or Pseudomonas having the ability to asymmetrically hydrolyze said ester linkage, a culture of said microorganism, a treated material from said microorganism, an enzyme produced by said microorganism, or an enzyme derived from swine or cattle.According to the present invention, there is provided a process for easily producing optically active 3-quinuclidinol derivatives which are important synthetic intermediates for pharmaceutical preparations etc.

Abstract: The disclosure relates to a process for obtaining optically active L-.alpha.-aminocarboxylic acids from the corresponding racemic D,L,.alpha.-aminocarboxylic acids. The following steps are involved: (a) the D,L,.alpha.-aminocarboxylic acids are acetylated; (b) the N-acetyl-L-.alpha.-aminocarboxylic acid present in the mixture of N-acetyl-D,L,.alpha.-aminocarboxylic acids thus obtained is broken down enzymatically into the L-.alpha.-aminocarboxylic acid; (c) the L-.alpha.-aminocarboxylic acid is separated from the mixture, a quantity of a solution of N-acetyl-D(L)-.alpha.-aminocarboxylic acids and a quantity of acetate equivalent to the L-.alpha.-aminocarboxylic acid being retained; and (d) the N-acetyl-D(L)-.alpha.-aminocarboxylic acid is racemized and recycled for enzymatic breakdown. Known extraction processes involving steps (a) to (d) have the disadvantage of producing large quantities of salt.

Abstract: An (R)-2-amino-1-phenylethanol derivative shown by the general formula (IIa) ##STR1## wherein R.sup.1 and R.sup.5 represent a hydrogen atom, etc.; R.sup.2, R.sup.3 and R.sup.4 independently represent a halogen atom, etc., or a salt thereof, can readily be produced (1) by permitting a Microorganism belonging to the genus Rhodosporidium, the genus Comamonas or the like to act on a mixture of corresponding (R)-form and (S)-form to asymmetrically utilize, or (2) by permitting a microorganism belonging to the genus Lodderomyces, the genus Pilimelia or the like to act on a corresponding aminoketone derivative to asymmetrically reduce. An (R,R)-1-phenyl-2-[(2-phenyl-1-alkylethyl) amino]ethanol derivative having a high optical purity can easily be obtained from the compound of the formula (IIa) or a salt thereof. Said derivative is useful as an intermediate for producing an anti-obesity agent and so on.

Abstract: A stereoselective method for making compounds of Formula VIII ##STR1## wherein A and * are as defined in the specification. Enzymic processes and intermediates useful for preparing compound of Formula VIII are disclosed.

Abstract: A process for the production of R-configuration or S-configuration optically active alcohol having the formula (1),CH.sub.3 C*H(OH)(CH.sub.2).sub.m OC.sub.n H.sub.2n+1 (1)wherein m is an integer of 3 to 5, n is an integer of 1 to 3, and C* is an asymmetric carbon,and the formula (2), which comprises carrying out the optical resolution of the racemic alcohol,CH.sub.3 CH(OH)(CH.sub.2).sub.m OC.sub.n H.sub.2n+1 (2)wherein m is an integer of 3 to 5 and n is an integer of 1 to 3,into an R-configuration compound and S-configuration compound by the asymmetric trans-esterification thereof is provided in the presence of vinyl propionate as an esterifying agent and a lipase as a catalyst.

Abstract: A lactamase enzyme having good stability, capable of hydrolysing an enatiomer of the bicyclic lactam, 2-azabicyclo[2.2.1]hept-5-en-3-one, to give (-) lactam and (+) amino acid, has been found in a strain of Comamonas acidivorans. The enzyme has been isolated and cloned, and its structure identified.

Abstract: Disclosed is a process for preparing acylated amino esters and a process for preparing optically active amino esters from racemic amino esters with a carboxylic ester as acylating agent, whose acid component has a halogen, nitrogen, oxygen or sulfur atom neighboring the carbonyl carbon atom, in the presence of a hydrolase selected from the group of amidase, protease, esterase and lipase, and subsequent separation of the enantioselectively acylated amino ester from the non-acylated other enantiomer of the amino ester.

Abstract: Optically active chroman-3-acetic acids and optically active chroman-3-acetic acid esters can be obtained by treating a mixture of (3R)- and (3S)-chroman-3-acetic esters of formula (I) ##STR1## [wherein R.sub.1 is a straight or branched alkyl group having 1-5 carbon atoms and R.sub.2 is a hydrogen atom or substituted or unsubstituted amino group]is treated with an esterase which has an optically selective hydrolyzing activity or microorganisms which carry said hydrolase, or a preparation therefrom. A novel esterase derived from bacteria of genus Pseudonocardia can also be used as said esterase.

Abstract: A purified (S)-hydroxy-nitrile-lyase is disclosed. Also disclosed is an amino acid sequence for (S)-hydroxy-nitrile-lyase and DNA sequence encoding the same.

Abstract: The invention relates to a process for preparing a substituted (6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)piperidine compound of the formula (+)-I ##STR1## wherein: R, R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are independently selected from the group consisting of hydrogen, halo, C.sub.1 -C.sub.6 alkyl, amino, --OCH.sub.3, --OCF.sub.3 and CF.sub.3, and the dotted line represents an optional double bond; comprising:enzymatically catalyzing the acylation of a compound of the formula (.+-.)-II ##STR2## wherein the variables are as defined above, and hydrolysing the product to obtain (+)-I.

Abstract: Optically active 1,2,4-butanetriol of high optical purity can be produced economically and simply using a microorganism capable of increasing the content of (S)-1,2,4-butanetriol or (R)-1,2,4-butanetriol by acting on a mixture of enantiomers of 1,2,4-butanetriol.

Abstract: (2R,3S)- and (2S,3R)-enantiomers of trans-.beta.-phenylglycidic esters, prepared by lipase-mediated enantioselective transesterification, are used for the synthesis of the taxol C-13 side chain with good yield.

Abstract: D-amino acid with high optical purity represented by formula (1-A) and/or formula (1-B), ##STR1## wherein R represents H or OH, ##STR2## wherein R.sub.1, R.sub.2 each represents H or OH, and amine represented by formula (2-A) and/or formula (2-B) ##STR3## wherein R represents H or OH, ##STR4## wherein R.sub.1 and R.sub.2 each represents H or OH, can be produced economically in an industrial scale by contacting a mixture of enantiomers of amino acid represented by the above formula (1-A) and/or formula (1-B) with a microorganism capable of selectively degrading L-amino acid or with at least one of the treated products of the microorganism.

Abstract: A novel enzyme is provided. This enzyme is capable of reducing 4-haloacetoacetic acid esters to produce (S)-4-halo-3-hydroxybutyric acid esters with high optical purity. The enzyme was isolated from a microorganism belonging to the genus Kluyveromyces. Using the enzyme, (S)-4-halo-3-hydroxybutyric acid esters, which are useful as HMG-CoA reductase inhibitors, intermediates for synthesizing various medicines and agricultural chemicals, can be efficiently produced with high optical purity.

Abstract: A compound of formula (III) ##STR1## is produced by selectively reducing a compound of formula (II) ##STR2## using a reductase possessing the properties of one produced by Beauveria, Candida, Kluyveromyces, Torulaspora or Pichia.orA compound of formula ##STR3## is produced by selectively reducing a compound of formula II using a reductase possessing the properties of one produced by Candida pelliculosa, Neurospora crassa, Pichia trehalophila or preferably Hansenula anomola.

Abstract: A process for preparing optically active allylic alcohol derivatives comprises reacting a racemic mixture of the following formula I ##STR1## wherein R is alkyl, alkenyl, or substituted or unsubstituted aryl or arylalkyl;with acetate or anhydride under the catalysis of Pseudomonase AK, PS or K-10 lipase in the presence of an organic solvent.

Abstract: A biocatalytic process to produce optically active phenylalanine analogs from arylacrylic acids is disclosed in which Rhodotorula graminis yeast containing phenylalanine ammonia-lyase introduces a molecule of ammonia stereoselectively onto the double bond of a 3-substituted acrylic acid. The substituent at the 3-position of the 3-substituted acrylic acid includes, for example, aromatic rings such as substituted phenyl groups, five member aromatic heterocyclics, and six member aromatic heterocyclics.

Abstract: Racemic amines are enzymically converted by enantioselective carbamation to produce to chiral carbamates. Simple homocarbonates employed as substrates. The chiral carbamates may then be deprotected to yield the original amine in a chiral form. Alternatively, the chiral carbamates may be reduced so as to produce methylated chiral amines.

Abstract: A method of preparing (+)-calanolide A, 1, a potent HIV reverse transcriptase inhibitor, from chromene 4 is provided. According to the disclosed method, chromene 4 intermediate was subjected to a chlorotitanium-mediated aldol reaction with acetaldehyde to selectively produce (.+-.)-8a. Separation and enzyme-mediated resolution of (.+-.)-8a produced (+)-8a. Cyclization of (+)-8a under neutral Mitsunobu conditions followed by Luche reduction of (+)-7 produced (+)-calanolide A in high yield and enantiomeric purity. The method of the invention has been extended to produce potent antiviral calanolide A analogues.

Abstract: There is provided a method for improving optical purity of an amine compound of the formula I: ##STR1## wherein R.sup.1 indicates a phenyl group which may be substituted or an aralkyl group having 7 to 10 carbon atoms which may be substituted, and R.sup.2 indicates an alkyl group having 1 to 6 carbon atoms, which is characterized by contacting a cutlture of a microorganism belonging to Arthrobacter having an ability to preferentially metabolize one optical isomer based on an asymmetric carbon atom to which an amino group bonds in the amine compound of the formula I or a treated product thereof with the amine compound of the formula I.

Abstract: A process for the efficient production of a D-amino acid from the corresponding DL-5-substituted hydantoin by one-step reaction which comprises using a composite immobilized enzyme at a pH about neutrality, said composite immobilized enzyme being obtained by immobilizing a hydantoinase having its optimal pH within an alkaline range and a D-N-carbamyl-.alpha.-amino acid amidohydrolase having its optimal pH about neutrality in a coexisting state on an immobilizing support, simultaneously, is disclosed.

Abstract: Optically active 2-substituted tetrahydropyran-4-ols or esters thereof may be prepared using esterases or hydrolases from the corresponding racemic mixtures of esters or alcohols. This provides a route to the corresponding optically active ketones.The racemic mixtures are preferably in the cis-form. such mixtures may be produced by reacting but-3-ene-1-ol with an aldehyde in the presence of an acid.

Abstract: A bioconversion process where benzyl acetoacetate is converted to benzyl-(S)-(+)-3-hydroxybutyrate.

Abstract: The present invention relates to a process for the enzymatic resolution of racemic mixtures of N-(alkoxycarbonyl)-4-keto-D,L-proline alkyl esters, using Candida antarctica lipase fraction B (CALB) as enzyme catalyst to enantioselectively hydrolyze the alkyl ester of one of the two enantiomers present. Separating the unreacted N-(alkoxycarbonyl)-4-keto-D-proline alkyl ester from the N-(alkoxycarbonyl)-4-keto-L-proline, followed by hydrogenation of the keto group of the D-isomer and subsequent hydrolysis of the ester and N-(alkoxy-carbonyl) groups produces cis-4-hydroxy-D-proline in high yield. Diastereomeric mixtures of N-(alkoxycarbonyl)-4-hydroxyproline alkyl esters can also be resolved using CALB to ultimately produce cis-4-hydroxy-D-proline or trans-4-hydroxy-L-proline.

Abstract: A process for the microbiological or enzymatic hydrolytic resolution of racemic trans-2-(alkoxycarbonylethyl) lactams of the formula I: ##STR1## wherein R is C.sub.1 -C.sub.7 alkyl, 2,2,2-trifluoroethyl or methoxyethoxyethyl and R.sup.1 is hydrogen or a protecting group is disclosed, whereby an optically enriched compound of the formula Ib or IIa: ##STR2## is obtained.

Abstract: The method for producing D-tryptophan with high optical purity and high yield is provided, which comprises contacting a mixture of D,L-tryptophan with organisms which produce tryptophanase to degrade L-tryptophan selectively, thereby increasing the content of D-tryptophan in D,L-tryptophan.

Abstract: The invention relates to an enzymatic process for the stereoselective preparation of a hetero-bicyclic alcohol enantiomer, characterized in that a substantially pure enantiomer of the general formula ##STR1## wherein X is O, S, NH, N--(C.sub.1 -C.sub.4)alkyl or CH.sub.2 ; Y.sub.1, Y.sub.2 and Y.sub.3 are each independently hydrogen or substituents selected from halogen, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 haloalkyl, nitro and cyano;the NO.sub.2 substituent is attached to the bicyclic ring system in the 5- or 7-position; andthe C*-atom has either the R or the S configuration;is prepared from its corresponding alcohol racemate by the following successive reaction steps:(1) stereoselective esterification,(2) separation of the alcohol from the ester produced,(3) hydrolysis of the ester to produce the corresponding alcohol enantiomer, and(4) conversion of the alcohol enantiomer into the starting racemate under basic conditions in order to allow its reuse.

Abstract: An organism of the genus Ophiostoma or Ceratocystis, or a material having enzymatic activity derived therefrom, is used as a stereo-specific agent, in a biotransformation reaction, for the production of an enantiomeric acid or alcohol from a mixture of enantiomers of an ester thereof.

Abstract: An enzymatic reduction method, particularly a stereoselective enzymatic reduction method, for the preparation of halohydrins from haloketones. The halohydrin products are particularly useful in the preparation of epoxides, which may be employed as intermediates in the preparation of protease inhibitors such as retroviral protease inhibitors.