Debra S. Perlow's research while affiliated with Merck & Co. and other places
What is this page?
This page lists the scientific contributions of an author, who either does not have a ResearchGate profile, or has not yet added these contributions to their profile.
It was automatically created by ResearchGate to create a record of this author's body of work. We create such pages to advance our goal of creating and maintaining the most comprehensive scientific repository possible. In doing so, we process publicly available (personal) data relating to the author as a member of the scientific community.
If you're a ResearchGate member, you can follow this page to keep up with this author's work.
If you are this author, and you don't want us to display this page anymore, please let us know.
It was automatically created by ResearchGate to create a record of this author's body of work. We create such pages to advance our goal of creating and maintaining the most comprehensive scientific repository possible. In doing so, we process publicly available (personal) data relating to the author as a member of the scientific community.
If you're a ResearchGate member, you can follow this page to keep up with this author's work.
If you are this author, and you don't want us to display this page anymore, please let us know.
Publications (21)
Structure-activity studies on the oxytocin antagonist 1 (L-371,257; Ki = 9.3 nM) have led to the identification of a related series of compounds containing an ortho-trifluoroethoxyphenylacetyl core which are orally bioavailable and have significantly improved potency in vitro and in vivo, e.g., compound 8 (L-374,943; Ki = 1.4 nM).
Lactam-bridged dipeptides are useful tools for the introduction of conformational constraint in higher peptides. General methods have been devised for the synthesis of dipeptides having five-, six-, and seven-membered ring constraints (1,2). This chapter will focus on four synthetic paths from protected chiral a-amino acids to lactams that involve...
Structure-activity studies on the oxytocin antagonist 1 (L-371,257) have identified a new series of high affinity, receptor-selective OT antagonists in which the N-acetyl-4-piperidinyl ether terminus in 1 has been replaced with a 1-(aryl)ethoxy group.
A series of new o-tolylpiperazine camphorsulfonamide OT antagonists is described. Analogs containing conformationally constrained 1-acylamino-2-propyl substituents at the camphor C2 endo position exhibit high affinity for OT and AVP-V1a receptors or high affinity and selectivity for OT receptors, depending on functionalities present in the acyl gro...
A new structural class of cyclic hexapeptide oxytocin antagonists derived from Streptomyces silvensis and typified by L-365,209 (cyclo-[L-prolyl1-D-phenylalanyl2-L- isoleucyl3-D-dehydropiperazyl4-L-dehydroperazyl5-D-(N- methyl)phenylalanyl6]) was recently reported. In this paper we further delineate the structure-activity profile for this new class...
Fmoc amino acid chlorides have been shown to be useful reagents in the solid-phase synthesis of hexapeptides containing up to four sequential secondary amino acids. The oxytocin antagonist cyclo-(D-Phe-Ile-D-Pip-Pip-D-(N-Me)Phe-Pro) (1) was prepared in 70% overall yield starting from Boc-L-Pro-O-(PAM)-resin. In the synthesis of 1, the high reactivi...
A series of renin inhibitors containing lactam-bridged P1-P1' dipeptide mimetics based on the ACHPA (4(S)-amino-5-cyclohexyl-3(S)-hydroxypentanoic acid) design was studied. The inhibitors were obtained by aldol addition of various lactams with N alpha-Boc-L-cyclohexylalaninal, followed by Boc group removal and acylation with Boc-Phe-His. The aldol...
The clinical efficacy of converting enzyme inhibitors1 for reducing blood pressure in a large percentage of hypertensive patients has aroused considerable interest in developing agents that interrupt the renin-angiotensin system at other points, for example by blockade of the angiotensin II receptor2 or by inhibition of the aspartic proteinase, ren...
Tachykinins are a family of peptides that share the carboxyl-terminal sequence Phe-X-Gly-Leu-Met-NH2 and that cause contraction of various smooth muscle systems. Substance P (Chang and Leeman, 1970) and the newly discovered neurokinin A (Maggio et al., 1983; Minamino et al., 1984a; Kimura et al., 1983) and neurokinin B* (Kimura et al., 1983; Kangaw...
The interaction between mouse submaxillary gland renin and a statine-containing, iodinated substrate analog inhibitor was studied. The compound, 1 (Boc-His-Pro-Phe-(4-iodo)-Phe-Sta-Leu-Phe-NH2, Sta = (3S,4S)-4-amino-3-hydroxy-6-methyl-heptanoic acid), a statine-containing analog of the renin substrate octapeptide, was a competitive inhibitor of cle...
The cyclic hexapeptide, cyclo (Pro-Phe-D-Trp-Lys-Thr-Phe), I, has been shown to have the biological properties of somatostatin. We now report structure-activity studies which optimize the potency of this cyclic hexapeptide series with the synthesis of cyclo (N-Me-Ala-Tyr-D-Trp-Lys-Val-Phe), II, which is 50-100 times more potent than somatostatin fo...
A model for the bioactive conformation of the highly active cyclic hexapeptide somatostatin analog cyclo-(Pro-Phe-D-Trp-Lys-Thr-Phe) has been proposed. As a test of this model, several compounds containing lactam and N-Me amino acid conformational modifications in the Thr-Phe-Pro-Phe beta turn were synthesized. The N-Me alanine and sarcosine substi...
General methods have been devised for the synthesis of lactam-constrained dipeptide analogues having five-, six-, and seven-membered rings. Three different paths from protected chiral α-amino acids to lactams involving intramolecular alkylation, intramolecular acylation, and insertion of a one carbon unit by condensation with formaldehyde have been...
Conformational analysis has resulted in the design and synthesis of somatostatin analogues which show increased duration of action1-3. The introduction of covalent conformational constraints and elimination of amino acids that are not required led to the synthesis of the highly active bicyclic analogue I, cyclo(Aha-Cys-Phe-D-Trp-Lys-Thr-Cys)2,3, wh...
An analog of luteinizing hormone-releasing hormone containing a gamma-lactam as a conformational constraint has been prepared with the use of a novel cyclization of a methionine sulfonium salt. The analog is more active as a luteinizing hormone-releasing hormone agonist that the parent hormone, and provides evidence for a bioactive conformation con...
Citations
... Inclusion of the cyclohexylalanyl analog of statin, (3S, 4S)-4-amino-5-cyclohexyl-3-hydroxypentanoic acid (ACHPA), to the octapeptide derivatives contributed the most powerful renin inhibitors. 25 Potency was retained even with the pentapeptides. 25 A series of tetrapeptides containing statins, with the addition of various hydrophobic aromatic groups at the carboxy terminus showed competitive renin inhibition. ...
... Freidinger et al. [58,59] and other groups [60,61] synthesized several analogs of bioactive peptides using their β-turn mimic, which were similar to the original bioactive peptides both structurally and in terms of bioactivity confirming its capacity as an effective mimic for a cis peptide bond. The same group later reported the synthesis of other similar δ and ε lactams using a very similar protocol [62] Bicyclic lactam amino acid, 2(S)-2,3,4,4a,7,7a-hexahydro-6-oxo-5Hpyrano [2,3-b]-pyrrole) was chosen as the most suitable mimic [63]. Synthesis of 26 from the pthalimido compound (27) was reported by the same group in a succeeding publication. ...
... Ben-Ishai first noticed that oxazolidin-5-ones were susceptible to nucleophil (Scheme 4a) [49]; the N-methylol amide could be easily transformed to N-methyla ide via palladium-catalyzed hydrogenation [49] or reduction with triethylsila Ben-Ishai first noticed that oxazolidin-5-ones were susceptible to nucleophilic attack (Scheme 4a) [49]; the N-methylol amide could be easily transformed to N-methylated amide via palladium-catalyzed hydrogenation [49] or reduction with triethylsilane/TFA combination [50]. Freidinger and co-workers further optimized this method, directly reductive ring-opening to furnish the protected N-methylated amino acids was achieved in one-pot and single step of reaction in the presence of triethylsilane/trifluoroacetic acid (TFA) (Scheme 4b) [51]. This technique was applicable to the synthesis of N-Fmocor N-Cbzprotected NMAAs [52,53] and has already been extended for the preparation of N-Boc-protected NMAAs in neutral reaction conditions by utilizing a mild hydrogenation procedure [54]. ...
... Marine natural products remain an important source of lead compounds for the development of novel pharmaceuticals and inspiration for the development of new synthetic strategies for their construction. Two recent examples of marine natural products include incarnatapeptins A (1) and B (2), Scheme 1, first reported by Ryan and Andersen in 2020 following the genome mining of Streptomyces sp. and 15 N NMR-based screening method. [1] Their structure is unique and characterized by a piperazic-acid-containing peptide connected to a unique polyketide-derived 3,5dimethyl-2,6-dioxabicyclo[2.2.2]octane moiety. ...
Reference: Total Synthesis of Incarnatapeptins A and B
... The identical carboxy OH and CO are the acceptor atoms and are spaced three bonds apart from the nitrogen atom in the proline. Furthermore, according to William J. Greenlee, the carboxy part engaged in interaction with the zinc atom at the active site (Greenlee et al., 1985). Therefore, the QSAR results are analogous with the reported findings. ...
![[object Object]](https://i1.rgstatic.net/ii/profile.image/273683088408582-1442262541924_Q64/William-Greenlee.jpg)
... According to the known OT physiological effects, highly specific OT antagonists may be of great therapeutic value for the prevention of preterm labor [57,58]. To date, many OT antagonists have been developed, the relatively efficient of which is a drug called Retosiban. ...
Reference: Oxytocin and Pregnancy
... Biosynthesis of 3-HB using direct 3-hydroxyacid pathway by functionally expressing wild-type genes in a well-characterized E. coli host has been successful in the past (Guevara-Martínez et al. 3-Hydroxyvalerate (3-HV) is a five carbon, optically active 3-HA and, much like 3-HB, is readily used in the pharmaceutical industry as a building block for chiral drug production (i.e., renin inhibitors) (Williams et al. 1991). While PHB contains a high degree of crystallinity and melting temperature, its industrial applications are limited due to structural inflexibility which makes subsequent processing a challenging task (Luo et al. 2006;Matsusaki et al. 2000). ...
... The elevated levels of SST receptors on NE neoplasms, as well as SST's antiangiogenic effects has led to the development of radiotheranostic analogs of SST. Peptide receptor radionuclide therapy derivatives have been targeting SST based on the biologically-active tetrapeptide Phe-Trp-Lys-Thr for receptor recognition [21,22]. While Zn(γ,p) 67 -14 and SST-28 exhibit significant affinity for all SST receptor subtypes, shorter analogs exclusively engage with the initial subgroup of receptor subtypes SST2, SST3, and SST5. ...
... In 1987 VanB inst and co-workers [55] synthesized and investigated by 500 MHz 2D NMR spectroscopy the preferred conformation of as tructural mimetic variant of the highly active cyclopeptidea nalogue of somatostatin, an effective inhibitor of growth hormoner elease, namely cyclo[Xxx-l-Phe-d-Trp-l-Lys-l-Thr-Yyy],k nownt oi nclude a cis amide bond between the Yyy and Xxx residues. [56] Their variant cyclopeptidei sc haracterized by an ortho-AMPA[ whereA MPAi sa n( aminomethyl)phenylacetyl] spacer,w hich mimics a-Gly-Gly-unit with a cis pseudopeptide bond as ar eplacement for the Yyy-Xxx dipeptide sequence (Figure 6a and b). In addition to the well known type-II' b-turn encompassing the -d-Trp-l-Lys-sequence, [56] the authorsp roposed the predominant occurrenceo fa ni ntramolecular Hbond connecting the NÀHa nd C=Og roups of the ortho-AMPA bridge, generating ap seudo-C 8 (d-turn) local conformer.H owever, it is important to mention here that Amblard and co-workers [57] quite convincingly reported that peptidomimetics characterized by the ortho-AMPAs pacer are more inclined to fold into ap seudo-C 10 (b-turn) form (Figure 6c). ...
... An exhaustive review collecting 125 cyclic peptides reported that only a few peptides are marketed drugs, and even fewer are orally absorbed [144]. The commercially available orally administered peptides are all short and cyclic peptides (e.g., cyclosporine-the immunosuppressant, desmopressin-the antidiabetic, linaclotide-for chronic idiopathic constipation, vancomycin hydrochloride and colistin sulfate-antibiotics, taltirelin hydrate-for spinocerebellar degeneration, glutathione-for AIDS-related cachexia and cystic fibrosis and tyrothricin-for pharyngitis) [145]. In 2019 FDA approved the Novo-Nordisk insulin, semaglutide, as the first orally available GLP-1 receptor agonist. ...
